<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:019b7fad-57b3-77c6-8796-dc32455779aa,g:3feb90f9-15ee-4193-aa43-beb833de7d4c-->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/all" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member"/>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/CondensedConsolidatedBalanceSheetsParenthetical" xlink:type="simple" xlink:href="rytm-20260331.xsd#CondensedConsolidatedBalanceSheetsParenthetical"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/CondensedConsolidatedBalanceSheetsParenthetical" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementTable_019b7fad-585b-73f6-91eb-7dda27d5613d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_StatementTable_019b7fad-585b-73f6-91eb-7dda27d5613d" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-75f5-8cf8-cad8074ed353" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementClassOfStockAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_StatementTable_019b7fad-585b-73f6-91eb-7dda27d5613d" xlink:to="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-75f5-8cf8-cad8074ed353" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-75f5-8cf8-cad8074ed353_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-75f5-8cf8-cad8074ed353" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-75f5-8cf8-cad8074ed353_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-79fb-8729-7bfbbdf4fa41" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-75f5-8cf8-cad8074ed353" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-79fb-8729-7bfbbdf4fa41" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SeriesAConvertiblePreferredStockMember_019de001-d322-755e-85cb-d023b76a70a2" xlink:href="rytm-20260331.xsd#rytm_SeriesAConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-79fb-8729-7bfbbdf4fa41" xlink:to="loc_rytm_SeriesAConvertiblePreferredStockMember_019de001-d322-755e-85cb-d023b76a70a2" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityParOrStatedValuePerShare_019b7fad-585b-711b-8228-9d8b7930916c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityParOrStatedValuePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_TemporaryEquityParOrStatedValuePerShare_019b7fad-585b-711b-8228-9d8b7930916c" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesAuthorized_019b7fad-585b-7a2f-af95-84f954c0c202" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesAuthorized"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_TemporaryEquitySharesAuthorized_019b7fad-585b-7a2f-af95-84f954c0c202" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesIssued_019b7fad-585b-7e78-a1bc-7913e8f47333" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesIssued"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_TemporaryEquitySharesIssued_019b7fad-585b-7e78-a1bc-7913e8f47333" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesOutstanding_019b7fad-585b-7c0a-b9b2-fcbb6f295349" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesOutstanding"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_TemporaryEquitySharesOutstanding_019b7fad-585b-7c0a-b9b2-fcbb6f295349" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityLiquidationPreference_019b7fad-585b-7cd9-8006-b38c9c0289ed" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityLiquidationPreference"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_TemporaryEquityLiquidationPreference_019b7fad-585b-7cd9-8006-b38c9c0289ed" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockParOrStatedValuePerShare_019df3ad-9864-79e7-a2ae-adbd6b63d1ca" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockParOrStatedValuePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_PreferredStockParOrStatedValuePerShare_019df3ad-9864-79e7-a2ae-adbd6b63d1ca" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockSharesAuthorized_019df3ad-9864-754b-bce7-597e70efcd68" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockSharesAuthorized"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_PreferredStockSharesAuthorized_019df3ad-9864-754b-bce7-597e70efcd68" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockSharesOutstanding_019df3ad-9864-7596-9e32-fa6caf796908" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockSharesOutstanding"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_PreferredStockSharesOutstanding_019df3ad-9864-7596-9e32-fa6caf796908" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockSharesIssued_019df3ad-9864-7e23-86cc-69f27f499217" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockSharesIssued"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_PreferredStockSharesIssued_019df3ad-9864-7e23-86cc-69f27f499217" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockParOrStatedValuePerShare_019b7fad-585b-7749-aee4-a88bdbf12678" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockParOrStatedValuePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_CommonStockParOrStatedValuePerShare_019b7fad-585b-7749-aee4-a88bdbf12678" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockSharesAuthorized_019b7fad-585b-7714-ad93-f72613104969" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockSharesAuthorized"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_CommonStockSharesAuthorized_019b7fad-585b-7714-ad93-f72613104969" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockSharesIssued_019b7fad-585b-7674-9b41-3c476f67e048" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockSharesIssued"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_CommonStockSharesIssued_019b7fad-585b-7674-9b41-3c476f67e048" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockSharesOutstanding_019b7fad-585b-7deb-9cfb-ab770d8db3e8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockSharesOutstanding"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-70ec-86a9-27bad8b9b34e" xlink:to="loc_us-gaap_CommonStockSharesOutstanding_019b7fad-585b-7deb-9cfb-ab770d8db3e8" xlink:type="arc" order="12"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/CondensedConsolidatedStatementsofOperationsandComprehensiveLoss" xlink:type="simple" xlink:href="rytm-20260331.xsd#CondensedConsolidatedStatementsofOperationsandComprehensiveLoss"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/CondensedConsolidatedStatementsofOperationsandComprehensiveLoss" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementTable_019b7fad-585b-726b-8987-38f5755d7e06" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_StatementTable_019b7fad-585b-726b-8987-38f5755d7e06" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductOrServiceAxis_019b7fad-585b-7a78-a08d-431e6bff7743" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductOrServiceAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_StatementTable_019b7fad-585b-726b-8987-38f5755d7e06" xlink:to="loc_srt_ProductOrServiceAxis_019b7fad-585b-7a78-a08d-431e6bff7743" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7a78-a08d-431e6bff7743_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_ProductOrServiceAxis_019b7fad-585b-7a78-a08d-431e6bff7743" xlink:to="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7a78-a08d-431e6bff7743_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7450-96c1-8917e532a0c4" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_ProductOrServiceAxis_019b7fad-585b-7a78-a08d-431e6bff7743" xlink:to="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7450-96c1-8917e532a0c4" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProductMember_019b7fad-585b-79e3-8dc8-eb8e1f718743" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProductMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7450-96c1-8917e532a0c4" xlink:to="loc_us-gaap_ProductMember_019b7fad-585b-79e3-8dc8-eb8e1f718743" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LicenseMember_019b7fad-585b-7fda-b7eb-a79e56748716" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LicenseMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_ProductsAndServicesDomain_019b7fad-585b-7450-96c1-8917e532a0c4" xlink:to="loc_us-gaap_LicenseMember_019b7fad-585b-7fda-b7eb-a79e56748716" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-585b-7802-b67b-1288bb1f48a0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-585b-7802-b67b-1288bb1f48a0" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostsAndExpensesAbstract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostOfGoodsAndServicesSold_019b7fad-585b-7d4c-8664-6fa107aa1de1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostOfGoodsAndServicesSold"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:to="loc_us-gaap_CostOfGoodsAndServicesSold_019b7fad-585b-7d4c-8664-6fa107aa1de1" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ResearchAndDevelopmentExpense_019b7fad-585b-74bb-a058-a6b752b950d9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ResearchAndDevelopmentExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:to="loc_us-gaap_ResearchAndDevelopmentExpense_019b7fad-585b-74bb-a058-a6b752b950d9" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SellingGeneralAndAdministrativeExpense_019b7fad-585b-7cec-b848-4034c290a48b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SellingGeneralAndAdministrativeExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:to="loc_us-gaap_SellingGeneralAndAdministrativeExpense_019b7fad-585b-7cec-b848-4034c290a48b" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostsAndExpenses_019b7fad-585b-7c50-8a63-ff0e3f3b4081" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostsAndExpenses"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CostsAndExpensesAbstract_019b7fad-585b-7b5c-8b88-b659318950fc" xlink:to="loc_us-gaap_CostsAndExpenses_019b7fad-585b-7c50-8a63-ff0e3f3b4081" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingIncomeLoss_019b7fad-585b-7dcb-87f9-fba3c8828db8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingIncomeLoss"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_OperatingIncomeLoss_019b7fad-585b-7dcb-87f9-fba3c8828db8" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonoperatingIncomeExpenseAbstract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherNonoperatingIncomeExpense_019b7fad-585b-7544-bcb2-58b6a5eb06ec" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherNonoperatingIncomeExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:to="loc_us-gaap_OtherNonoperatingIncomeExpense_019b7fad-585b-7544-bcb2-58b6a5eb06ec" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_InterestExpenseNonoperating_019b7fad-585b-7fb9-8e83-b593cc66f804" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InterestExpenseNonoperating"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:to="loc_us-gaap_InterestExpenseNonoperating_019b7fad-585b-7fb9-8e83-b593cc66f804" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_InvestmentIncomeNet_019b7fad-585b-7ec7-981e-a7917933fe3a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InvestmentIncomeNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:to="loc_us-gaap_InvestmentIncomeNet_019b7fad-585b-7ec7-981e-a7917933fe3a" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonoperatingIncomeExpense_019b7fad-585b-75cc-b336-e9f53356b327" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonoperatingIncomeExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_NonoperatingIncomeExpenseAbstract_019b7fad-585b-785e-8b20-4ef9b8fb36eb" xlink:to="loc_us-gaap_NonoperatingIncomeExpense_019b7fad-585b-75cc-b336-e9f53356b327" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019b7fad-585b-70d1-864a-9b8b2f501dc7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019b7fad-585b-70d1-864a-9b8b2f501dc7" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit_019b7fad-585b-7c3a-ae8d-830c9b4c4e05" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeTaxExpenseBenefit"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_IncomeTaxExpenseBenefit_019b7fad-585b-7c3a-ae8d-830c9b4c4e05" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLoss_019b7fad-585b-7887-9b5d-d75d5ae3cfd5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_NetIncomeLoss_019b7fad-585b-7887-9b5d-d75d5ae3cfd5" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ConvertiblePreferredStockDividends_019b7fad-585b-7b6f-b82e-3506081b9a6a" xlink:href="rytm-20260331.xsd#rytm_ConvertiblePreferredStockDividends"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_rytm_ConvertiblePreferredStockDividends_019b7fad-585b-7b6f-b82e-3506081b9a6a" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic_019b7fad-585b-71ef-bbbf-bdf4bf397115" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic_019b7fad-585b-71ef-bbbf-bdf4bf397115" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EarningsPerShareBasic_019b7fad-585b-78bc-8bab-f5711ccb43f7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EarningsPerShareBasic"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_EarningsPerShareBasic_019b7fad-585b-78bc-8bab-f5711ccb43f7" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EarningsPerShareDiluted_019b7fad-585b-700d-8c7f-3814b23c5256" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EarningsPerShareDiluted"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_EarningsPerShareDiluted_019b7fad-585b-700d-8c7f-3814b23c5256" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_019b7fad-585b-7805-8133-88236e67a3d9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_019b7fad-585b-7805-8133-88236e67a3d9" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_019b7fad-585b-7bbf-8805-7728ac000e57" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_019b7fad-585b-7bbf-8805-7728ac000e57" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract_019b7fad-585b-726c-ad18-edcef19ec7a7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7839-8065-dc8e27fadbdc" xlink:to="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract_019b7fad-585b-726c-ad18-edcef19ec7a7" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic_019b7fad-585b-7235-b0b2-b2059c3a765c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax_019b7fad-585b-7495-bfc8-1e7e59163a7b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract_019b7fad-585b-726c-ad18-edcef19ec7a7" xlink:to="loc_us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax_019b7fad-585b-7495-bfc8-1e7e59163a7b" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossAvailableForSaleSecuritiesAdjustmentNetOfTax_019b7fad-585b-7592-830d-9c7761550c9a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeLossAvailableForSaleSecuritiesAdjustmentNetOfTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract_019b7fad-585b-726c-ad18-edcef19ec7a7" xlink:to="loc_us-gaap_OtherComprehensiveIncomeLossAvailableForSaleSecuritiesAdjustmentNetOfTax_019b7fad-585b-7592-830d-9c7761550c9a" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ComprehensiveIncomeNetOfTax_019b7fad-585b-7e3e-b56e-3e0d91a9d390" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ComprehensiveIncomeNetOfTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTaxPeriodIncreaseDecreaseAbstract_019b7fad-585b-726c-ad18-edcef19ec7a7" xlink:to="loc_us-gaap_ComprehensiveIncomeNetOfTax_019b7fad-585b-7e3e-b56e-3e0d91a9d390" xlink:type="arc" order="4"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/CondensedConsolidatedStatementsofConvertiblePreferredStockStockholdersEquity" xlink:type="simple" xlink:href="rytm-20260331.xsd#CondensedConsolidatedStatementsofConvertiblePreferredStockStockholdersEquity"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/CondensedConsolidatedStatementsofConvertiblePreferredStockStockholdersEquity" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementLineItems_019b7fad-585b-7c50-950e-a5f00b7368e1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementTable_019b7fad-585b-799a-aba2-a4ed83473e5d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7c50-950e-a5f00b7368e1" xlink:to="loc_us-gaap_StatementTable_019b7fad-585b-799a-aba2-a4ed83473e5d" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementEquityComponentsAxis_019b7fad-585b-73a2-a836-b035ce93fcfe" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_StatementTable_019b7fad-585b-799a-aba2-a4ed83473e5d" xlink:to="loc_us-gaap_StatementEquityComponentsAxis_019b7fad-585b-73a2-a836-b035ce93fcfe" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_019b7fad-585b-73a2-a836-b035ce93fcfe_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_019b7fad-585b-73a2-a836-b035ce93fcfe" xlink:to="loc_us-gaap_EquityComponentDomain_019b7fad-585b-73a2-a836-b035ce93fcfe_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_019b7fad-585b-73a2-a836-b035ce93fcfe" xlink:to="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockMember_019b7fad-585b-7e8d-b69a-bc673fd45779" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:to="loc_us-gaap_CommonStockMember_019b7fad-585b-7e8d-b69a-bc673fd45779" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdditionalPaidInCapitalMember_019b7fad-585b-70c1-abf5-789bfc731495" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdditionalPaidInCapitalMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:to="loc_us-gaap_AdditionalPaidInCapitalMember_019b7fad-585b-70c1-abf5-789bfc731495" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccumulatedOtherComprehensiveIncomeMember_019b7fad-585b-7666-aecb-dd4ab1062db0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:to="loc_us-gaap_AccumulatedOtherComprehensiveIncomeMember_019b7fad-585b-7666-aecb-dd4ab1062db0" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RetainedEarningsMember_019b7fad-585b-70df-9028-0cfc2f14523d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RetainedEarningsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_019b7fad-585b-7457-a888-2e89c2ae6b04" xlink:to="loc_us-gaap_RetainedEarningsMember_019b7fad-585b-70df-9028-0cfc2f14523d" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-7383-a48a-2ff103aed157" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementClassOfStockAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_StatementTable_019b7fad-585b-799a-aba2-a4ed83473e5d" xlink:to="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-7383-a48a-2ff103aed157" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-7383-a48a-2ff103aed157_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-7383-a48a-2ff103aed157" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-7383-a48a-2ff103aed157_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-7859-bd9a-8db96b61b35f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-585b-7383-a48a-2ff103aed157" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-7859-bd9a-8db96b61b35f" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SeriesAConvertiblePreferredStockMember_019d3054-85e1-7373-8305-e7b14c01987d" xlink:href="rytm-20260331.xsd#rytm_SeriesAConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockDomain_019b7fad-585b-7859-bd9a-8db96b61b35f" xlink:to="loc_rytm_SeriesAConvertiblePreferredStockMember_019d3054-85e1-7373-8305-e7b14c01987d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityAbstract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7c50-950e-a5f00b7368e1" xlink:to="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesOutstanding_019b7fad-585b-7817-a969-d2666c66c8ba" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesOutstanding"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:to="loc_us-gaap_TemporaryEquitySharesOutstanding_019b7fad-585b-7817-a969-d2666c66c8ba" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityCarryingAmountAttributableToParent_019b7fad-585b-77df-9f47-e7fab458b0cc" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityCarryingAmountAttributableToParent"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:to="loc_us-gaap_TemporaryEquityCarryingAmountAttributableToParent_019b7fad-585b-77df-9f47-e7fab458b0cc" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019db0c7-19f4-7fcc-bfe0-245bfeaaea61" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquitySharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:to="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019db0c7-19f4-7fcc-bfe0-245bfeaaea61" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityValueConversionOfConvertibleSecurities_019db0c7-19f4-76bc-833b-8874ea75a5c0" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityValueConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:to="loc_rytm_TemporaryEquityValueConversionOfConvertibleSecurities_019db0c7-19f4-76bc-833b-8874ea75a5c0" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityAccretionOfDividends_019b7fad-585b-71e2-84cb-5a7dbdcfee07" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityAccretionOfDividends"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityAbstract_019b7fad-585b-7fe5-9556-c153241e662e" xlink:to="loc_us-gaap_TemporaryEquityAccretionOfDividends_019b7fad-585b-71e2-84cb-5a7dbdcfee07" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesOutstanding_019b7fad-585b-71ff-b529-a3aee579f52e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesOutstanding"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityCarryingAmountAttributableToParent_019b7fad-585b-7bc7-8872-db3e595e6fa9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityCarryingAmountAttributableToParent"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInStockholdersEquityRollForward"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_StatementLineItems_019b7fad-585b-7c50-950e-a5f00b7368e1" xlink:to="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockSharesIssued_019db0a7-ddb3-7f15-8612-688ebacfd73c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockSharesIssued"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_CommonStockSharesIssued_019db0a7-ddb3-7f15-8612-688ebacfd73c" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockholdersEquity_019b7fad-585b-7b7c-b51c-bfbff0ebe6b2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockholdersEquity"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockholdersEquity_019b7fad-585b-7b7c-b51c-bfbff0ebe6b2" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue_019b7fad-585b-7b16-bd57-61167510794e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue_019b7fad-585b-7b16-bd57-61167510794e" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans_019b7fad-585b-7d7a-9e13-56cc3205a06a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans_019b7fad-585b-7d7a-9e13-56cc3205a06a" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan_019b7fad-585b-7ade-8d91-397859ec405e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan_019b7fad-585b-7ade-8d91-397859ec405e" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StockIssuedDuringPeriodSharesStockOptionsAndRestrictedStockUnitsVesting_019b7fad-585b-7302-81d6-b337acd2b901" xlink:href="rytm-20260331.xsd#rytm_StockIssuedDuringPeriodSharesStockOptionsAndRestrictedStockUnitsVesting"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_rytm_StockIssuedDuringPeriodSharesStockOptionsAndRestrictedStockUnitsVesting_019b7fad-585b-7302-81d6-b337acd2b901" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StockIssuedDuringPeriodValueStockOptionsAndRestrictedStockUnitsVesting_019b7fad-585b-7558-8fa5-15cd0d3f67e4" xlink:href="rytm-20260331.xsd#rytm_StockIssuedDuringPeriodValueStockOptionsAndRestrictedStockUnitsVesting"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_rytm_StockIssuedDuringPeriodValueStockOptionsAndRestrictedStockUnitsVesting_019b7fad-585b-7558-8fa5-15cd0d3f67e4" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_019db0cf-9e72-784a-8d37-0182b6665dbf" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_019db0cf-9e72-784a-8d37-0182b6665dbf" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation_019db0cf-54f7-7845-9bb5-f2a8c297c1a4" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation_019db0cf-54f7-7845-9bb5-f2a8c297c1a4" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019db0c7-19f4-7164-a8db-86c1a3bb3d98" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019db0c7-19f4-7164-a8db-86c1a3bb3d98" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities_019db0c7-19f4-7c9f-8b02-66a9c9dbbc77" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities_019db0c7-19f4-7c9f-8b02-66a9c9dbbc77" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdjustmentsToAdditionalPaidInCapitalDividendsInExcessOfRetainedEarnings_019b7fad-585b-762e-9997-cc748d1a3d99" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalDividendsInExcessOfRetainedEarnings"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_AdjustmentsToAdditionalPaidInCapitalDividendsInExcessOfRetainedEarnings_019b7fad-585b-762e-9997-cc748d1a3d99" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesNewIssues_019b7fad-585b-757a-9223-640a6a6a3f8d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesNewIssues_019b7fad-585b-757a-9223-640a6a6a3f8d" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019b7fad-585b-79d4-8dd3-66fd8ecd7f18" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019b7fad-585b-79d4-8dd3-66fd8ecd7f18" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax_019b7fad-585b-740a-8339-6ebdeafdbd8d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax_019b7fad-585b-740a-8339-6ebdeafdbd8d" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax_019d3054-85e1-71bb-af5c-ac46fd34b9e9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax_019d3054-85e1-71bb-af5c-ac46fd34b9e9" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLoss_019b7fad-585b-7944-bb44-fe6267d59642" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward_019b7fad-585b-7b75-b375-37de3e520189" xlink:to="loc_us-gaap_NetIncomeLoss_019b7fad-585b-7944-bb44-fe6267d59642" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockSharesIssued_019db0a8-ba7c-79c7-8d32-77418e6f487f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockSharesIssued"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockholdersEquity_019b7fad-585b-7751-9df0-e8ba0ac4b9eb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockholdersEquity"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SummaryofSignificantAccountingPoliciesOffBalanceSheetRiskandConcentrationsofCreditRiskDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SummaryofSignificantAccountingPoliciesOffBalanceSheetRiskandConcentrationsofCreditRiskDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SummaryofSignificantAccountingPoliciesOffBalanceSheetRiskandConcentrationsofCreditRiskDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProductInformationLineItems_019d3077-c65d-7660-b31f-ce31ff11c226" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProductInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfProductInformationTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_ProductInformationLineItems_019d3077-c65d-7660-b31f-ce31ff11c226" xlink:to="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_MajorCustomersAxis_019d3077-c65d-7ca2-a1b0-27c57dcab8ff" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_MajorCustomersAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:to="loc_srt_MajorCustomersAxis_019d3077-c65d-7ca2-a1b0-27c57dcab8ff" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7ca2-a1b0-27c57dcab8ff_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_NameOfMajorCustomerDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_MajorCustomersAxis_019d3077-c65d-7ca2-a1b0-27c57dcab8ff" xlink:to="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7ca2-a1b0-27c57dcab8ff_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7dc2-8075-ffc015f6c8f6" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_NameOfMajorCustomerDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_MajorCustomersAxis_019d3077-c65d-7ca2-a1b0-27c57dcab8ff" xlink:to="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7dc2-8075-ffc015f6c8f6" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CustomerOneMember_019d3077-c65d-7fce-a8e9-fb4067e279d0" xlink:href="rytm-20260331.xsd#rytm_CustomerOneMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7dc2-8075-ffc015f6c8f6" xlink:to="loc_rytm_CustomerOneMember_019d3077-c65d-7fce-a8e9-fb4067e279d0" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CustomerTwoMember_019db0da-9dfe-7611-9b62-3695ed17a5e3" xlink:href="rytm-20260331.xsd#rytm_CustomerTwoMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_NameOfMajorCustomerDomain_019d3077-c65d-7dc2-8075-ffc015f6c8f6" xlink:to="loc_rytm_CustomerTwoMember_019db0da-9dfe-7611-9b62-3695ed17a5e3" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskByBenchmarkAxis_019d3077-c65d-7a6e-95c6-ddcd48865b8d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskByBenchmarkAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:to="loc_us-gaap_ConcentrationRiskByBenchmarkAxis_019d3077-c65d-7a6e-95c6-ddcd48865b8d" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7a6e-95c6-ddcd48865b8d_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskBenchmarkDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_ConcentrationRiskByBenchmarkAxis_019d3077-c65d-7a6e-95c6-ddcd48865b8d" xlink:to="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7a6e-95c6-ddcd48865b8d_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7518-9983-426a1d394324" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskBenchmarkDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_ConcentrationRiskByBenchmarkAxis_019d3077-c65d-7a6e-95c6-ddcd48865b8d" xlink:to="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7518-9983-426a1d394324" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SalesRevenueNetMember_019d3077-c65d-7cfe-af6f-c056ef2ee0af" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SalesRevenueNetMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7518-9983-426a1d394324" xlink:to="loc_us-gaap_SalesRevenueNetMember_019d3077-c65d-7cfe-af6f-c056ef2ee0af" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccountsReceivableMember_019d3077-c65d-7593-a8e2-56401636854a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccountsReceivableMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ConcentrationRiskBenchmarkDomain_019d3077-c65d-7518-9983-426a1d394324" xlink:to="loc_us-gaap_AccountsReceivableMember_019d3077-c65d-7593-a8e2-56401636854a" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskByTypeAxis_019d3077-c65d-7b0e-a9ce-77b91687fea9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskByTypeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:to="loc_us-gaap_ConcentrationRiskByTypeAxis_019d3077-c65d-7b0e-a9ce-77b91687fea9" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskTypeDomain_019d3077-c65d-7b0e-a9ce-77b91687fea9_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_ConcentrationRiskByTypeAxis_019d3077-c65d-7b0e-a9ce-77b91687fea9" xlink:to="loc_us-gaap_ConcentrationRiskTypeDomain_019d3077-c65d-7b0e-a9ce-77b91687fea9_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskTypeDomain_019d3077-c65d-7583-97e9-a122066f0541" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_ConcentrationRiskByTypeAxis_019d3077-c65d-7b0e-a9ce-77b91687fea9" xlink:to="loc_us-gaap_ConcentrationRiskTypeDomain_019d3077-c65d-7583-97e9-a122066f0541" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CustomerConcentrationRiskMember_019d3077-c65d-7616-b26a-f7332fd6b191" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CustomerConcentrationRiskMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ConcentrationRiskTypeDomain_019d3077-c65d-7583-97e9-a122066f0541" xlink:to="loc_us-gaap_CustomerConcentrationRiskMember_019d3077-c65d-7616-b26a-f7332fd6b191" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductOrServiceAxis_019d3077-c65d-7ff3-a205-a6b6058c5cda" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductOrServiceAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfProductInformationTable_019d3077-c65d-73c0-add0-53452e0abd78" xlink:to="loc_srt_ProductOrServiceAxis_019d3077-c65d-7ff3-a205-a6b6058c5cda" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019d3077-c65d-7ff3-a205-a6b6058c5cda_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_ProductOrServiceAxis_019d3077-c65d-7ff3-a205-a6b6058c5cda" xlink:to="loc_srt_ProductsAndServicesDomain_019d3077-c65d-7ff3-a205-a6b6058c5cda_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019d3077-c65d-7868-b13f-1e1ffd18a409" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_ProductOrServiceAxis_019d3077-c65d-7ff3-a205-a6b6058c5cda" xlink:to="loc_srt_ProductsAndServicesDomain_019d3077-c65d-7868-b13f-1e1ffd18a409" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_NumberOfFederallyInsuredFinancialInstitutions_019d3077-c65d-79dd-b3af-42b8f3c5359f" xlink:href="rytm-20260331.xsd#rytm_NumberOfFederallyInsuredFinancialInstitutions"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ProductInformationLineItems_019d3077-c65d-7660-b31f-ce31ff11c226" xlink:to="loc_rytm_NumberOfFederallyInsuredFinancialInstitutions_019d3077-c65d-79dd-b3af-42b8f3c5359f" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConcentrationRiskPercentage1_019d3077-c65d-7173-aba7-82a2a2c37f03" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConcentrationRiskPercentage1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ProductInformationLineItems_019d3077-c65d-7660-b31f-ce31ff11c226" xlink:to="loc_us-gaap_ConcentrationRiskPercentage1_019d3077-c65d-7173-aba7-82a2a2c37f03" xlink:type="arc" order="1"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SummaryofSignificantAccountingPoliciesNetlosspershareDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SummaryofSignificantAccountingPoliciesNetlosspershareDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SummaryofSignificantAccountingPoliciesNetlosspershareDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems_019b7fad-585b-7c49-8007-23030057c362" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable_019b7fad-585b-7d72-8a4a-c2df91b6b3d4" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems_019b7fad-585b-7c49-8007-23030057c362" xlink:to="loc_us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable_019b7fad-585b-7d72-8a4a-c2df91b6b3d4" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable_019b7fad-585b-7d72-8a4a-c2df91b6b3d4" xlink:to="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AntidilutiveSecuritiesNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1" xlink:to="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AntidilutiveSecuritiesNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis_019b7fad-585b-76c3-8a0e-1a4d44dc4ae1" xlink:to="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EmployeeStockOptionMember_019b7fad-585b-7d0d-ae50-f029048fc216" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmployeeStockOptionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:to="loc_us-gaap_EmployeeStockOptionMember_019b7fad-585b-7d0d-ae50-f029048fc216" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RestrictedStockUnitsRSUMember_019b7fad-585b-7eab-8b5f-94ae709bbaea" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedStockUnitsRSUMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:to="loc_us-gaap_RestrictedStockUnitsRSUMember_019b7fad-585b-7eab-8b5f-94ae709bbaea" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PerformanceSharesMember_019b7fad-585b-76d7-8b20-48375da7f521" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PerformanceSharesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:to="loc_us-gaap_PerformanceSharesMember_019b7fad-585b-76d7-8b20-48375da7f521" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SeriesAConvertiblePreferredStockMember_019de003-5e1e-7316-9ca3-c1e5d86d28e9" xlink:href="rytm-20260331.xsd#rytm_SeriesAConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AntidilutiveSecuritiesNameDomain_019b7fad-585b-73dc-9824-1618b4f6c702" xlink:to="loc_rytm_SeriesAConvertiblePreferredStockMember_019de003-5e1e-7316-9ca3-c1e5d86d28e9" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount_019b7fad-585b-72d1-adb6-2fe41603ab0c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems_019b7fad-585b-7c49-8007-23030057c362" xlink:to="loc_us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount_019b7fad-585b-72d1-adb6-2fe41603ab0c" xlink:type="arc" order="0"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/AssetAcquisitionsNarrativeDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#AssetAcquisitionsNarrativeDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/AssetAcquisitionsNarrativeDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetAcquisitionLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetAcquisitionTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_CounterpartyNameAxis_019d307c-5818-71ca-b121-f16ed63f8722" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_CounterpartyNameAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:to="loc_srt_CounterpartyNameAxis_019d307c-5818-71ca-b121-f16ed63f8722" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RepurchaseAgreementCounterpartyNameDomain_019d307c-5818-71ca-b121-f16ed63f8722_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RepurchaseAgreementCounterpartyNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_CounterpartyNameAxis_019d307c-5818-71ca-b121-f16ed63f8722" xlink:to="loc_srt_RepurchaseAgreementCounterpartyNameDomain_019d307c-5818-71ca-b121-f16ed63f8722_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RepurchaseAgreementCounterpartyNameDomain_019d307c-5818-77c6-a137-4177b3b65136" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RepurchaseAgreementCounterpartyNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_CounterpartyNameAxis_019d307c-5818-71ca-b121-f16ed63f8722" xlink:to="loc_srt_RepurchaseAgreementCounterpartyNameDomain_019d307c-5818-77c6-a137-4177b3b65136" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LGChemLtdMember_019d307c-5818-7d51-a071-38e5650fc78c" xlink:href="rytm-20260331.xsd#rytm_LGChemLtdMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_RepurchaseAgreementCounterpartyNameDomain_019d307c-5818-77c6-a137-4177b3b65136" xlink:to="loc_rytm_LGChemLtdMember_019d307c-5818-7d51-a071-38e5650fc78c" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TypeOfArrangementAxis_019d307c-5818-7e25-a10e-5afc20be6d2a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TypeOfArrangementAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:to="loc_us-gaap_TypeOfArrangementAxis_019d307c-5818-7e25-a10e-5afc20be6d2a" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d307c-5818-7e25-a10e-5afc20be6d2a_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_TypeOfArrangementAxis_019d307c-5818-7e25-a10e-5afc20be6d2a" xlink:to="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d307c-5818-7e25-a10e-5afc20be6d2a_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d307c-5818-74ea-b885-140da79a4ca5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_TypeOfArrangementAxis_019d307c-5818-7e25-a10e-5afc20be6d2a" xlink:to="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d307c-5818-74ea-b885-140da79a4ca5" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LicenseAgreementAndShareIssuanceAgreementMember_019d307c-5818-70f0-8f42-5d6066bbe4cf" xlink:href="rytm-20260331.xsd#rytm_LicenseAgreementAndShareIssuanceAgreementMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d307c-5818-74ea-b885-140da79a4ca5" xlink:to="loc_rytm_LicenseAgreementAndShareIssuanceAgreementMember_019d307c-5818-70f0-8f42-5d6066bbe4cf" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationAxis_019d307c-5818-7a27-be75-232402142715" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:to="loc_us-gaap_IncomeStatementLocationAxis_019d307c-5818-7a27-be75-232402142715" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7a27-be75-232402142715_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_IncomeStatementLocationAxis_019d307c-5818-7a27-be75-232402142715" xlink:to="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7a27-be75-232402142715_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7411-b723-ca5c22c7d329" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_IncomeStatementLocationAxis_019d307c-5818-7a27-be75-232402142715" xlink:to="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7411-b723-ca5c22c7d329" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SellingGeneralAndAdministrativeExpensesMember_019d307c-5818-7baa-a58e-baa4692512f3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SellingGeneralAndAdministrativeExpensesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7411-b723-ca5c22c7d329" xlink:to="loc_us-gaap_SellingGeneralAndAdministrativeExpensesMember_019d307c-5818-7baa-a58e-baa4692512f3" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ResearchAndDevelopmentExpenseMember_019d307d-a801-72ca-a67e-5559e2e1cfd3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ResearchAndDevelopmentExpenseMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncomeStatementLocationDomain_019d307c-5818-7411-b723-ca5c22c7d329" xlink:to="loc_us-gaap_ResearchAndDevelopmentExpenseMember_019d307d-a801-72ca-a67e-5559e2e1cfd3" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetAcquisitionAxis_019d307c-5818-7ce5-b5f8-30ed7392ab2d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetAcquisitionAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_AssetAcquisitionTable_019d307b-a49c-7fc9-a0fd-ecc5cfb9c65f" xlink:to="loc_us-gaap_AssetAcquisitionAxis_019d307c-5818-7ce5-b5f8-30ed7392ab2d" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetAcquisitionDomain_019d307c-5818-7ce5-b5f8-30ed7392ab2d_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetAcquisitionDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_AssetAcquisitionAxis_019d307c-5818-7ce5-b5f8-30ed7392ab2d" xlink:to="loc_us-gaap_AssetAcquisitionDomain_019d307c-5818-7ce5-b5f8-30ed7392ab2d_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetAcquisitionDomain_019d307c-5818-73a0-a231-f264ab75bd11" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetAcquisitionDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_AssetAcquisitionAxis_019d307c-5818-7ce5-b5f8-30ed7392ab2d" xlink:to="loc_us-gaap_AssetAcquisitionDomain_019d307c-5818-73a0-a231-f264ab75bd11" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LGChemLtdMember_019d307c-5818-72d0-8ee2-33fa8e85e147" xlink:href="rytm-20260331.xsd#rytm_LGChemLtdMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionDomain_019d307c-5818-73a0-a231-f264ab75bd11" xlink:to="loc_rytm_LGChemLtdMember_019d307c-5818-72d0-8ee2-33fa8e85e147" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_BusinessCombinationConsiderationTransferred1_019d307c-5818-7cec-b26f-f3566446b58a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_BusinessCombinationConsiderationTransferred1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_BusinessCombinationConsiderationTransferred1_019d307c-5818-7cec-b26f-f3566446b58a" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PaymentsToAcquireBusinessesNetOfCashAcquired_019d307c-5818-77a8-b367-b3bab867481d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsToAcquireBusinessesNetOfCashAcquired"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_PaymentsToAcquireBusinessesNetOfCashAcquired_019d307c-5818-77a8-b367-b3bab867481d" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019d307c-5818-7411-94bd-e8d5c7a3e890" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019d307c-5818-7411-94bd-e8d5c7a3e890" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ThresholdPeriodForCalculatingWeightedAverageClosingPricePerShare_019d307c-5818-7f06-8920-125e8df5c137" xlink:href="rytm-20260331.xsd#rytm_ThresholdPeriodForCalculatingWeightedAverageClosingPricePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_ThresholdPeriodForCalculatingWeightedAverageClosingPricePerShare_019d307c-5818-7f06-8920-125e8df5c137" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StockIssuedDuringPeriodValueNewIssuesLicenseAgreement_019d307c-5818-7c33-be0c-492842070097" xlink:href="rytm-20260331.xsd#rytm_StockIssuedDuringPeriodValueNewIssuesLicenseAgreement"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_StockIssuedDuringPeriodValueNewIssuesLicenseAgreement_019d307c-5818-7c33-be0c-492842070097" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LicenseAgreementConsiderationPaymentReceivedInCash_019d307c-5818-7bf4-bf6d-ceaa1e415001" xlink:href="rytm-20260331.xsd#rytm_LicenseAgreementConsiderationPaymentReceivedInCash"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_LicenseAgreementConsiderationPaymentReceivedInCash_019d307c-5818-7bf4-bf6d-ceaa1e415001" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LockUpPeriodForSubsequentCashPayment_019d307c-5818-70c5-9aeb-ac99d604c833" xlink:href="rytm-20260331.xsd#rytm_LockUpPeriodForSubsequentCashPayment"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_LockUpPeriodForSubsequentCashPayment_019d307c-5818-70c5-9aeb-ac99d604c833" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccountsPayableFairValueDisclosure_019d307c-5818-7f63-8c51-b8b3a4139457" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccountsPayableFairValueDisclosure"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_AccountsPayableFairValueDisclosure_019d307c-5818-7f63-8c51-b8b3a4139457" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_BusinessCombinationAcquisitionRelatedCosts_019d307c-5818-7b6f-b03b-ba959b72f660" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_BusinessCombinationAcquisitionRelatedCosts"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_us-gaap_BusinessCombinationAcquisitionRelatedCosts_019d307c-5818-7b6f-b03b-ba959b72f660" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_PaymentForAdditionalConsiderationOnAssetAcquisition_019d307c-5818-70e8-b7f7-e4b8e7f82a9f" xlink:href="rytm-20260331.xsd#rytm_PaymentForAdditionalConsiderationOnAssetAcquisition"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_PaymentForAdditionalConsiderationOnAssetAcquisition_019d307c-5818-70e8-b7f7-e4b8e7f82a9f" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AggregatePaymentUponAchievementOfDevelopmentAndCommercialMilestones_019d307d-c7ab-7b15-bc75-6c65b3fb2489" xlink:href="rytm-20260331.xsd#rytm_AggregatePaymentUponAchievementOfDevelopmentAndCommercialMilestones"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetAcquisitionLineItems_019d307c-5818-76d7-ad6b-300a3c1b1bb7" xlink:to="loc_rytm_AggregatePaymentUponAchievementOfDevelopmentAndCommercialMilestones_019d307d-c7ab-7b15-bc75-6c65b3fb2489" xlink:type="arc" order="10"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesFinancialAssetsandLiabilitiesMeasuredatFairValueonaRecurringBasisDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#FairValueofFinancialAssetsandLiabilitiesFinancialAssetsandLiabilitiesMeasuredatFairValueonaRecurringBasisDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesFinancialAssetsandLiabilitiesMeasuredatFairValueonaRecurringBasisDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019d3084-50ec-7507-a975-34d4acc3a90f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019d3084-50ec-7753-98b0-10657d0db623" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019d3084-50ec-7507-a975-34d4acc3a90f" xlink:to="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019d3084-50ec-7753-98b0-10657d0db623" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019d3084-50ec-7dcc-8ee2-2f55832179ab" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019d3084-50ec-7753-98b0-10657d0db623" xlink:to="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019d3084-50ec-7dcc-8ee2-2f55832179ab" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7dcc-8ee2-2f55832179ab_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019d3084-50ec-7dcc-8ee2-2f55832179ab" xlink:to="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7dcc-8ee2-2f55832179ab_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7968-acc3-f899a337a092" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019d3084-50ec-7dcc-8ee2-2f55832179ab" xlink:to="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7968-acc3-f899a337a092" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueInputsLevel1Member_019d3084-50ec-7317-baba-0c71cbfafbcc" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueInputsLevel1Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7968-acc3-f899a337a092" xlink:to="loc_us-gaap_FairValueInputsLevel1Member_019d3084-50ec-7317-baba-0c71cbfafbcc" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueInputsLevel2Member_019d3084-50ec-74d7-a66b-278ee42b0d46" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueInputsLevel2Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7968-acc3-f899a337a092" xlink:to="loc_us-gaap_FairValueInputsLevel2Member_019d3084-50ec-74d7-a66b-278ee42b0d46" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueInputsLevel3Member_019d3084-50ec-79d6-b36c-b86cffdaefeb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueInputsLevel3Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019d3084-50ec-7968-acc3-f899a337a092" xlink:to="loc_us-gaap_FairValueInputsLevel3Member_019d3084-50ec-79d6-b36c-b86cffdaefeb" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CashAndCashEquivalentsAxis_019d3084-50ec-755f-95e4-d8b4638b71b7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashAndCashEquivalentsAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019d3084-50ec-7753-98b0-10657d0db623" xlink:to="loc_us-gaap_CashAndCashEquivalentsAxis_019d3084-50ec-755f-95e4-d8b4638b71b7" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-755f-95e4-d8b4638b71b7_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_CashAndCashEquivalentsAxis_019d3084-50ec-755f-95e4-d8b4638b71b7" xlink:to="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-755f-95e4-d8b4638b71b7_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-7d14-9566-203b5eb7261f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_CashAndCashEquivalentsAxis_019d3084-50ec-755f-95e4-d8b4638b71b7" xlink:to="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-7d14-9566-203b5eb7261f" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommercialPaperMember_019d3084-50ec-7809-bf41-e40f8c50983d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommercialPaperMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-7d14-9566-203b5eb7261f" xlink:to="loc_us-gaap_CommercialPaperMember_019d3084-50ec-7809-bf41-e40f8c50983d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_MoneyMarketFundsMember_019d3084-50ec-7cb9-968f-fbb434c88a5e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_MoneyMarketFundsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_019d3084-50ec-7d14-9566-203b5eb7261f" xlink:to="loc_us-gaap_MoneyMarketFundsMember_019d3084-50ec-7cb9-968f-fbb434c88a5e" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FinancialInstrumentAxis_019d3084-50ec-770c-b046-cdc5c67e9d64" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinancialInstrumentAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019d3084-50ec-7753-98b0-10657d0db623" xlink:to="loc_us-gaap_FinancialInstrumentAxis_019d3084-50ec-770c-b046-cdc5c67e9d64" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-770c-b046-cdc5c67e9d64_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_FinancialInstrumentAxis_019d3084-50ec-770c-b046-cdc5c67e9d64" xlink:to="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-770c-b046-cdc5c67e9d64_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-7f32-b140-b1c74494bd95" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_FinancialInstrumentAxis_019d3084-50ec-770c-b046-cdc5c67e9d64" xlink:to="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-7f32-b140-b1c74494bd95" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_USTreasurySecuritiesMember_019d3084-50ec-7bff-a653-2ab6f5f6888d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_USTreasurySecuritiesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-7f32-b140-b1c74494bd95" xlink:to="loc_us-gaap_USTreasurySecuritiesMember_019d3084-50ec-7bff-a653-2ab6f5f6888d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CorporateDebtSecuritiesAndCommercialPaperMember_019d3084-50ec-707b-a243-0db3d3857fee" xlink:href="rytm-20260331.xsd#rytm_CorporateDebtSecuritiesAndCommercialPaperMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019d3084-50ec-7f32-b140-b1c74494bd95" xlink:to="loc_rytm_CorporateDebtSecuritiesAndCommercialPaperMember_019d3084-50ec-707b-a243-0db3d3857fee" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetsFairValueDisclosureAbstract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019d3084-50ec-7507-a975-34d4acc3a90f" xlink:to="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CashAndCashEquivalentsFairValueDisclosure_019d3084-50ec-7e86-82bf-fef209f4fa69" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashAndCashEquivalentsFairValueDisclosure"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:to="loc_us-gaap_CashAndCashEquivalentsFairValueDisclosure_019d3084-50ec-7e86-82bf-fef209f4fa69" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AvailableForSaleSecuritiesDebtSecurities_019d3084-50ec-7600-a699-5d5dd118b4d6" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:to="loc_us-gaap_AvailableForSaleSecuritiesDebtSecurities_019d3084-50ec-7600-a699-5d5dd118b4d6" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DerivativeAssets_019d3084-50ec-7067-b207-0fb0f659b1ff" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DerivativeAssets"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:to="loc_us-gaap_DerivativeAssets_019d3084-50ec-7067-b207-0fb0f659b1ff" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetsFairValueDisclosure_019d3084-50ec-782a-a1af-5001f36c2c6a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetsFairValueDisclosure"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_AssetsFairValueDisclosureAbstract_019d3084-50ec-73ee-9afd-bc873e1679a4" xlink:to="loc_us-gaap_AssetsFairValueDisclosure_019d3084-50ec-782a-a1af-5001f36c2c6a" xlink:type="arc" order="4"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesChangesinEmbeddedDerivativeLiabilityDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#FairValueofFinancialAssetsandLiabilitiesChangesinEmbeddedDerivativeLiabilityDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesChangesinEmbeddedDerivativeLiabilityDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-78a5-8533-1cc4c938723c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-728b-aa7c-4cc209a516c5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-78a5-8533-1cc4c938723c" xlink:to="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-728b-aa7c-4cc209a516c5" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019b7fad-591b-7fea-9ce3-954335c1bb28" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-728b-aa7c-4cc209a516c5" xlink:to="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019b7fad-591b-7fea-9ce3-954335c1bb28" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019b7fad-591b-7fea-9ce3-954335c1bb28_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019b7fad-591b-7fea-9ce3-954335c1bb28" xlink:to="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019b7fad-591b-7fea-9ce3-954335c1bb28_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019b7fad-591b-71a5-80ff-10550e3ef5ef" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_FairValueByFairValueHierarchyLevelAxis_019b7fad-591b-7fea-9ce3-954335c1bb28" xlink:to="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019b7fad-591b-71a5-80ff-10550e3ef5ef" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueInputsLevel3Member_019b7fad-591b-7087-95f8-02bfb9bfb701" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueInputsLevel3Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueMeasurementsFairValueHierarchyDomain_019b7fad-591b-71a5-80ff-10550e3ef5ef" xlink:to="loc_us-gaap_FairValueInputsLevel3Member_019b7fad-591b-7087-95f8-02bfb9bfb701" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DerivativeInstrumentRiskAxis_019b7fad-591b-725e-b396-cd7d3f3686e6" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DerivativeInstrumentRiskAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-728b-aa7c-4cc209a516c5" xlink:to="loc_us-gaap_DerivativeInstrumentRiskAxis_019b7fad-591b-725e-b396-cd7d3f3686e6" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DerivativeContractTypeDomain_019b7fad-591b-725e-b396-cd7d3f3686e6_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DerivativeContractTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_DerivativeInstrumentRiskAxis_019b7fad-591b-725e-b396-cd7d3f3686e6" xlink:to="loc_us-gaap_DerivativeContractTypeDomain_019b7fad-591b-725e-b396-cd7d3f3686e6_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DerivativeContractTypeDomain_019b7fad-591b-7552-9cb1-220810751787" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DerivativeContractTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_DerivativeInstrumentRiskAxis_019b7fad-591b-725e-b396-cd7d3f3686e6" xlink:to="loc_us-gaap_DerivativeContractTypeDomain_019b7fad-591b-7552-9cb1-220810751787" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EmbeddedDerivativeFinancialInstrumentsMember_019b7fad-591b-7423-aaac-e7c4b63f12c9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmbeddedDerivativeFinancialInstrumentsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DerivativeContractTypeDomain_019b7fad-591b-7552-9cb1-220810751787" xlink:to="loc_us-gaap_EmbeddedDerivativeFinancialInstrumentsMember_019b7fad-591b-7423-aaac-e7c4b63f12c9" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward_019b7fad-591b-7d85-8db9-26977c6a4ccd" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-78a5-8533-1cc4c938723c" xlink:to="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward_019b7fad-591b-7d85-8db9-26977c6a4ccd" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityAssetValueBeginningBalance_019b7fad-591b-784b-a095-f27411ba9445" xlink:href="rytm-20260331.xsd#rytm_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityAssetValueBeginningBalance"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward_019b7fad-591b-7d85-8db9-26977c6a4ccd" xlink:to="loc_rytm_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityAssetValueBeginningBalance_019b7fad-591b-784b-a095-f27411ba9445" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityPeriodIncreaseDecrease_019b7fad-591b-7eae-9e55-9da037e6e446" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityPeriodIncreaseDecrease"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward_019b7fad-591b-7d85-8db9-26977c6a4ccd" xlink:to="loc_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityPeriodIncreaseDecrease_019b7fad-591b-7eae-9e55-9da037e6e446" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityAssetValueBeginningBalance_019b7fad-591b-7277-8f0c-7865871f3d54" xlink:href="rytm-20260331.xsd#rytm_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisLiabilityAssetValueBeginningBalance"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesMarketableSecuritiesDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#FairValueofFinancialAssetsandLiabilitiesMarketableSecuritiesDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/FairValueofFinancialAssetsandLiabilitiesMarketableSecuritiesDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-7a85-8734-af6f3593be9f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:to="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-7a85-8734-af6f3593be9f" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FinancialInstrumentAxis_019b7fad-591b-7204-84a7-631e39a43912" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinancialInstrumentAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable_019b7fad-591b-7a85-8734-af6f3593be9f" xlink:to="loc_us-gaap_FinancialInstrumentAxis_019b7fad-591b-7204-84a7-631e39a43912" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-7204-84a7-631e39a43912_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_FinancialInstrumentAxis_019b7fad-591b-7204-84a7-631e39a43912" xlink:to="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-7204-84a7-631e39a43912_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-754b-aed2-ed5803ac6a43" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_FinancialInstrumentAxis_019b7fad-591b-7204-84a7-631e39a43912" xlink:to="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-754b-aed2-ed5803ac6a43" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CorporateDebtSecuritiesAndCommercialPaperMember_019b7fad-591b-7cdc-969a-5fac5fc3e72a" xlink:href="rytm-20260331.xsd#rytm_CorporateDebtSecuritiesAndCommercialPaperMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-754b-aed2-ed5803ac6a43" xlink:to="loc_rytm_CorporateDebtSecuritiesAndCommercialPaperMember_019b7fad-591b-7cdc-969a-5fac5fc3e72a" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_USTreasurySecuritiesMember_019b7fad-591b-7261-9ca7-86030de2cb55" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_USTreasurySecuritiesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain_019b7fad-591b-754b-aed2-ed5803ac6a43" xlink:to="loc_us-gaap_USTreasurySecuritiesMember_019b7fad-591b-7261-9ca7-86030de2cb55" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis_019b7fad-591b-7474-a24a-9d13d988ab68" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:to="loc_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis_019b7fad-591b-7474-a24a-9d13d988ab68" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax_019b7fad-591b-722b-b8e5-e8515890a1c5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:to="loc_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax_019b7fad-591b-722b-b8e5-e8515890a1c5" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax_019b7fad-591b-76f1-a6ee-4c281beefbed" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:to="loc_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax_019b7fad-591b-76f1-a6ee-4c281beefbed" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AvailableForSaleSecuritiesDebtSecurities_019b7fad-591b-73d4-a3d4-941c171b169d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems_019b7fad-591b-72ed-93df-68b22778a04e" xlink:to="loc_us-gaap_AvailableForSaleSecuritiesDebtSecurities_019b7fad-591b-73d4-a3d4-941c171b169d" xlink:type="arc" order="3"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/IntangibleAssetsScheduleoffinitelivedintangibleassetsDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#IntangibleAssetsScheduleoffinitelivedintangibleassetsDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/IntangibleAssetsScheduleoffinitelivedintangibleassetsDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019b7fad-591b-7cd0-b178-b1fcd70b24c9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:to="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019b7fad-591b-7cd0-b178-b1fcd70b24c9" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019b7fad-591b-7856-bf59-55007ce52323" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019b7fad-591b-7cd0-b178-b1fcd70b24c9" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019b7fad-591b-7856-bf59-55007ce52323" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019b7fad-591b-7856-bf59-55007ce52323_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019b7fad-591b-7856-bf59-55007ce52323" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019b7fad-591b-7856-bf59-55007ce52323_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019b7fad-591b-7559-aa06-f613c50d8c0e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019b7fad-591b-7856-bf59-55007ce52323" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019b7fad-591b-7559-aa06-f613c50d8c0e" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CapitalizedMilestonesMember_019b7fad-591b-7a66-820e-28ac29a4705d" xlink:href="rytm-20260331.xsd#rytm_CapitalizedMilestonesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019b7fad-591b-7559-aa06-f613c50d8c0e" xlink:to="loc_rytm_CapitalizedMilestonesMember_019b7fad-591b-7a66-820e-28ac29a4705d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetUsefulLife_019b7fad-591b-719f-9274-3a65ccc92152" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetUsefulLife"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetUsefulLife_019b7fad-591b-719f-9274-3a65ccc92152" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsGross_019b7fad-591b-7f77-b201-d2ea4fc81c02" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsGross"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsGross_019b7fad-591b-7f77-b201-d2ea4fc81c02" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization_019b7fad-591b-7c4d-afe0-5fb5a315e407" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization_019b7fad-591b-7c4d-afe0-5fb5a315e407" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019b7fad-591b-7f7a-a5cb-3a4295de1394" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019b7fad-591b-7009-884c-e3a5881c8751" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019b7fad-591b-7f7a-a5cb-3a4295de1394" xlink:type="arc" order="3"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/IntangibleAssetsNarrativeDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#IntangibleAssetsNarrativeDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/IntangibleAssetsNarrativeDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019d3088-be14-76e0-9509-3f4d2da24f46" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019d3088-be14-75b4-b776-41c7ff8f0dc8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019d3088-be14-76e0-9509-3f4d2da24f46" xlink:to="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019d3088-be14-75b4-b776-41c7ff8f0dc8" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019d3088-be14-7d4c-8ac1-29f3aa67c389" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019d3088-be14-75b4-b776-41c7ff8f0dc8" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019d3088-be14-7d4c-8ac1-29f3aa67c389" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019d3088-be14-7d4c-8ac1-29f3aa67c389_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019d3088-be14-7d4c-8ac1-29f3aa67c389" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019d3088-be14-7d4c-8ac1-29f3aa67c389_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019d3088-be14-7c6f-a3bc-dd0301db93d0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsByMajorClassAxis_019d3088-be14-7d4c-8ac1-29f3aa67c389" xlink:to="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019d3088-be14-7c6f-a3bc-dd0301db93d0" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CapitalizedMilestonesMember_019d3088-be14-786e-9454-45d214b7c529" xlink:href="rytm-20260331.xsd#rytm_CapitalizedMilestonesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IndefiniteLivedIntangibleAssetsMajorClassNameDomain_019d3088-be14-7c6f-a3bc-dd0301db93d0" xlink:to="loc_rytm_CapitalizedMilestonesMember_019d3088-be14-786e-9454-45d214b7c529" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationAxis_019d3089-62dc-7381-9bea-23c028969d9e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable_019d3088-be14-75b4-b776-41c7ff8f0dc8" xlink:to="loc_us-gaap_IncomeStatementLocationAxis_019d3089-62dc-7381-9bea-23c028969d9e" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationDomain_019d3089-62dc-7381-9bea-23c028969d9e_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_IncomeStatementLocationAxis_019d3089-62dc-7381-9bea-23c028969d9e" xlink:to="loc_us-gaap_IncomeStatementLocationDomain_019d3089-62dc-7381-9bea-23c028969d9e_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeStatementLocationDomain_019d3089-62dc-7541-ab66-023198b4d1f6" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeStatementLocationDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_IncomeStatementLocationAxis_019d3089-62dc-7381-9bea-23c028969d9e" xlink:to="loc_us-gaap_IncomeStatementLocationDomain_019d3089-62dc-7541-ab66-023198b4d1f6" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostOfSalesMember_019d3089-62dc-76c0-8e8f-9a5c2194803f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostOfSalesMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_IncomeStatementLocationDomain_019d3089-62dc-7541-ab66-023198b4d1f6" xlink:to="loc_us-gaap_CostOfSalesMember_019d3089-62dc-76c0-8e8f-9a5c2194803f" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019d3088-be14-7e63-afc2-37f2bfff1a83" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019d3088-be14-76e0-9509-3f4d2da24f46" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019d3088-be14-7e63-afc2-37f2bfff1a83" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AmortizationOfIntangibleAssets_019d3089-62dc-761a-8208-78a11d23f25a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AmortizationOfIntangibleAssets"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsLineItems_019d3088-be14-76e0-9509-3f4d2da24f46" xlink:to="loc_us-gaap_AmortizationOfIntangibleAssets_019d3089-62dc-761a-8208-78a11d23f25a" xlink:type="arc" order="1"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SeriesAConvertiblePreferredStockDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SeriesAConvertiblePreferredStockDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SeriesAConvertiblePreferredStockDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityByClassOfStockTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementClassOfStockAxis_019b7fad-591b-7d7b-8edd-3f11d11974ea" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementClassOfStockAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:to="loc_us-gaap_StatementClassOfStockAxis_019b7fad-591b-7d7b-8edd-3f11d11974ea" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-591b-7d7b-8edd-3f11d11974ea_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-591b-7d7b-8edd-3f11d11974ea" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-591b-7d7b-8edd-3f11d11974ea_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019b7fad-591b-7590-83c4-f93747b7be2e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019b7fad-591b-7d7b-8edd-3f11d11974ea" xlink:to="loc_us-gaap_ClassOfStockDomain_019b7fad-591b-7590-83c4-f93747b7be2e" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SeriesAConvertiblePreferredStockMember_019d87b3-11ba-7519-9a3e-5845ead960d7" xlink:href="rytm-20260331.xsd#rytm_SeriesAConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockDomain_019b7fad-591b-7590-83c4-f93747b7be2e" xlink:to="loc_rytm_SeriesAConvertiblePreferredStockMember_019d87b3-11ba-7519-9a3e-5845ead960d7" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueByLiabilityClassAxis_019b7fad-591b-7301-a394-b35d908b61a0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueByLiabilityClassAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:to="loc_us-gaap_FairValueByLiabilityClassAxis_019b7fad-591b-7301-a394-b35d908b61a0" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain_019b7fad-591b-7301-a394-b35d908b61a0_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_FairValueByLiabilityClassAxis_019b7fad-591b-7301-a394-b35d908b61a0" xlink:to="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain_019b7fad-591b-7301-a394-b35d908b61a0_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain_019b7fad-591b-7fe0-b145-3ff55d0fb3aa" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_FairValueByLiabilityClassAxis_019b7fad-591b-7301-a394-b35d908b61a0" xlink:to="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain_019b7fad-591b-7fe0-b145-3ff55d0fb3aa" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ForwardContractsMember_019b7fad-591b-7068-afc3-9fd3afa1db82" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ForwardContractsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_FairValueLiabilitiesMeasuredOnRecurringBasisUnobservableInputReconciliationByLiabilityClassDomain_019b7fad-591b-7fe0-b145-3ff55d0fb3aa" xlink:to="loc_us-gaap_ForwardContractsMember_019b7fad-591b-7068-afc3-9fd3afa1db82" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ConvertiblePreferredStockHolderAxis_019db0f5-3d50-76b1-9cdd-338719e95dfb" xlink:href="rytm-20260331.xsd#rytm_ConvertiblePreferredStockHolderAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:to="loc_rytm_ConvertiblePreferredStockHolderAxis_019db0f5-3d50-76b1-9cdd-338719e95dfb" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-76b1-9cdd-338719e95dfb_default" xlink:href="rytm-20260331.xsd#rytm_ConvertiblePreferredStockHolderDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_rytm_ConvertiblePreferredStockHolderAxis_019db0f5-3d50-76b1-9cdd-338719e95dfb" xlink:to="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-76b1-9cdd-338719e95dfb_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-7137-919b-442631bf642d" xlink:href="rytm-20260331.xsd#rytm_ConvertiblePreferredStockHolderDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_rytm_ConvertiblePreferredStockHolderAxis_019db0f5-3d50-76b1-9cdd-338719e95dfb" xlink:to="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-7137-919b-442631bf642d" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_OneHolderOfSeriesConvertiblePreferredStockMember_019b7fad-591b-7dca-a556-ec93f64d8f45" xlink:href="rytm-20260331.xsd#rytm_OneHolderOfSeriesConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-7137-919b-442631bf642d" xlink:to="loc_rytm_OneHolderOfSeriesConvertiblePreferredStockMember_019b7fad-591b-7dca-a556-ec93f64d8f45" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SecondHolderOfSeriesConvertiblePreferredStockMember_019b7fad-591b-72d9-9bd1-b1c08df3cfca" xlink:href="rytm-20260331.xsd#rytm_SecondHolderOfSeriesConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_ConvertiblePreferredStockHolderDomain_019db0f5-3d50-7137-919b-442631bf642d" xlink:to="loc_rytm_SecondHolderOfSeriesConvertiblePreferredStockMember_019b7fad-591b-72d9-9bd1-b1c08df3cfca" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementEquityComponentsAxis_019d87b4-8783-76c9-be76-a7b4415a703b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_TemporaryEquityByClassOfStockTable_019b7fad-591b-7b2c-a9a8-4840bb8a8fbe" xlink:to="loc_us-gaap_StatementEquityComponentsAxis_019d87b4-8783-76c9-be76-a7b4415a703b" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_019d87b4-8783-76c9-be76-a7b4415a703b_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_019d87b4-8783-76c9-be76-a7b4415a703b" xlink:to="loc_us-gaap_EquityComponentDomain_019d87b4-8783-76c9-be76-a7b4415a703b_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_019d87b4-8783-72b4-913f-2a586185586d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_019d87b4-8783-76c9-be76-a7b4415a703b" xlink:to="loc_us-gaap_EquityComponentDomain_019d87b4-8783-72b4-913f-2a586185586d" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdditionalPaidInCapitalMember_019d87b4-8783-7567-97c9-50b446d8ac0a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdditionalPaidInCapitalMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_019d87b4-8783-72b4-913f-2a586185586d" xlink:to="loc_us-gaap_AdditionalPaidInCapitalMember_019d87b4-8783-7567-97c9-50b446d8ac0a" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues_019b7fad-591b-76ab-9275-67a57c0bcd1d" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues_019b7fad-591b-76ab-9275-67a57c0bcd1d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityParOrStatedValuePerShare_019b7fad-591b-7caf-8507-2c2ef61480cb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityParOrStatedValuePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityParOrStatedValuePerShare_019b7fad-591b-7caf-8507-2c2ef61480cb" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityAggregatePurchasePrice_019b7fad-591b-76f1-a94a-b0dc87923bdf" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityAggregatePurchasePrice"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityAggregatePurchasePrice_019b7fad-591b-76f1-a94a-b0dc87923bdf" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityStockIssuanceCost_019b7fad-591b-72f3-ba6a-0c45c6788039" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityStockIssuanceCost"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityStockIssuanceCost_019b7fad-591b-72f3-ba6a-0c45c6788039" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SharePrice_019b7fad-591b-75e4-81e5-8f5e52d2d3a9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SharePrice"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_SharePrice_019b7fad-591b-75e4-81e5-8f5e52d2d3a9" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquitySharesIssuedPricePerShare_019b7fad-591b-7a8b-8ef3-1d96246a8b6a" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquitySharesIssuedPricePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquitySharesIssuedPricePerShare_019b7fad-591b-7a8b-8ef3-1d96246a8b6a" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityContractTerms_019b7fad-591b-7b23-86f6-e4535feed8e2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityContractTerms"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityContractTerms_019b7fad-591b-7b23-86f6-e4535feed8e2" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DerivativeLiabilities_019b7fad-591b-752d-8dcc-5a651db73785" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DerivativeLiabilities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_DerivativeLiabilities_019b7fad-591b-752d-8dcc-5a651db73785" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityFairValueDisclosure_019b7fad-591b-7181-a7ec-6fc8af8d66df" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityFairValueDisclosure"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityFairValueDisclosure_019b7fad-591b-7181-a7ec-6fc8af8d66df" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019d87b3-11ba-7592-9cf5-fa96040e06a3" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquitySharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019d87b3-11ba-7592-9cf5-fa96040e06a3" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ConvertiblePreferredStockSharesIssuedUponConversion_019b7fad-591b-7349-96d5-3f557632111b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ConvertiblePreferredStockSharesIssuedUponConversion"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_ConvertiblePreferredStockSharesIssuedUponConversion_019b7fad-591b-7349-96d5-3f557632111b" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019d87b4-0a35-74f7-bb64-c8a819fa866d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019d87b4-0a35-74f7-bb64-c8a819fa866d" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities_019d87b4-8783-7e79-80f9-0cae86a99b48" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities_019d87b4-8783-7e79-80f9-0cae86a99b48" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityLiquidationPreferenceMultiplierFactor_019b7fad-591b-75a0-90b3-1ec8a7f2da30" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityLiquidationPreferenceMultiplierFactor"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityLiquidationPreferenceMultiplierFactor_019b7fad-591b-75a0-90b3-1ec8a7f2da30" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityLiquidationPreferencePerShare_019b7fad-591b-77a6-b05c-e800a312e61a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityLiquidationPreferencePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityLiquidationPreferencePerShare_019b7fad-591b-77a6-b05c-e800a312e61a" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityDividendRatePercentage_019b7fad-591b-78e3-b523-fa1b016159db" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityDividendRatePercentage"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_TemporaryEquityDividendRatePercentage_019b7fad-591b-78e3-b523-fa1b016159db" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityAccretionOfDividends_019b7fad-591b-772d-8706-a0ec5f2a970c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityAccretionOfDividends"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityAccretionOfDividends_019b7fad-591b-772d-8706-a0ec5f2a970c" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquityCarryingAmountAttributableToParent_019b7fad-591b-7a48-99fb-ab2fbe6cbec7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquityCarryingAmountAttributableToParent"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquityCarryingAmountAttributableToParent_019b7fad-591b-7a48-99fb-ab2fbe6cbec7" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockConvertibleConversionPrice_019b7fad-591b-7da2-b8bb-4b326e9d1a37" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockConvertibleConversionPrice"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_PreferredStockConvertibleConversionPrice_019b7fad-591b-7da2-b8bb-4b326e9d1a37" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_PercentageOfOwnershipAfterConversion_019b7fad-591b-7824-84e8-34979f70a800" xlink:href="rytm-20260331.xsd#rytm_PercentageOfOwnershipAfterConversion"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_PercentageOfOwnershipAfterConversion_019b7fad-591b-7824-84e8-34979f70a800" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_LimitedVotingRightsShares_019b7fad-591b-776e-b755-af56ae2c8ec2" xlink:href="rytm-20260331.xsd#rytm_LimitedVotingRightsShares"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_LimitedVotingRightsShares_019b7fad-591b-776e-b755-af56ae2c8ec2" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StepUpInterestRatePercentage_019b7fad-591b-7fb2-87a2-ee63e3ef831a" xlink:href="rytm-20260331.xsd#rytm_StepUpInterestRatePercentage"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_StepUpInterestRatePercentage_019b7fad-591b-7fb2-87a2-ee63e3ef831a" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_PreferredStockSharesAuthorizedIncludingTemporaryEquity_019df8b7-d5d7-7a91-8860-ba29dfec21c9" xlink:href="rytm-20260331.xsd#rytm_PreferredStockSharesAuthorizedIncludingTemporaryEquity"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_rytm_PreferredStockSharesAuthorizedIncludingTemporaryEquity_019df8b7-d5d7-7a91-8860-ba29dfec21c9" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TemporaryEquitySharesAuthorized_019df8a7-689a-78cb-9332-57c560f6b015" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TemporaryEquitySharesAuthorized"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_TemporaryEquityLineItems_019b7fad-591b-736d-9eda-c8dff395612b" xlink:to="loc_us-gaap_TemporaryEquitySharesAuthorized_019df8a7-689a-78cb-9332-57c560f6b015" xlink:type="arc" order="23"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/CommonStockDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#CommonStockDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/CommonStockDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfStockByClassTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PlanNameAxis_019d87c0-cec9-7449-bf31-aa8cdbc60fca" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PlanNameAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:to="loc_us-gaap_PlanNameAxis_019d87c0-cec9-7449-bf31-aa8cdbc60fca" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7449-bf31-aa8cdbc60fca_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PlanNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_PlanNameAxis_019d87c0-cec9-7449-bf31-aa8cdbc60fca" xlink:to="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7449-bf31-aa8cdbc60fca_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PlanNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_PlanNameAxis_019d87c0-cec9-7449-bf31-aa8cdbc60fca" xlink:to="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StockOptionsRestrictedStockUnitsPerformanceStockUnitsInAggregateMember_019d87c0-cec9-7f45-a970-fca053ffd1a1" xlink:href="rytm-20260331.xsd#rytm_StockOptionsRestrictedStockUnitsPerformanceStockUnitsInAggregateMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:to="loc_rytm_StockOptionsRestrictedStockUnitsPerformanceStockUnitsInAggregateMember_019d87c0-cec9-7f45-a970-fca053ffd1a1" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TwoThousandSeventeenEmployeeAndEmploymentInducementPlan2022stockPurchasePlansInAggregateMember_019d87c0-cec9-7749-93df-9fb952eb844f" xlink:href="rytm-20260331.xsd#rytm_TwoThousandSeventeenEmployeeAndEmploymentInducementPlan2022stockPurchasePlansInAggregateMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:to="loc_rytm_TwoThousandSeventeenEmployeeAndEmploymentInducementPlan2022stockPurchasePlansInAggregateMember_019d87c0-cec9-7749-93df-9fb952eb844f" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_StockIncentivePlan2017Member_019d87c0-cec9-7594-8783-9749432e1b15" xlink:href="rytm-20260331.xsd#rytm_StockIncentivePlan2017Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:to="loc_rytm_StockIncentivePlan2017Member_019d87c0-cec9-7594-8783-9749432e1b15" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TwoThousandSeventeenEmployeeStockPurchasePlanMember_019d87c0-cec9-781a-a1ee-096b22206238" xlink:href="rytm-20260331.xsd#rytm_TwoThousandSeventeenEmployeeStockPurchasePlanMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:to="loc_rytm_TwoThousandSeventeenEmployeeStockPurchasePlanMember_019d87c0-cec9-781a-a1ee-096b22206238" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_EmploymentInducementPlan2022Member_019d87c4-9e28-77d0-8cf3-4f2eb9a54bbd" xlink:href="rytm-20260331.xsd#rytm_EmploymentInducementPlan2022Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_PlanNameDomain_019d87c0-cec9-7cc5-b5cb-ab6bdda11116" xlink:to="loc_rytm_EmploymentInducementPlan2022Member_019d87c4-9e28-77d0-8cf3-4f2eb9a54bbd" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementClassOfStockAxis_019d87c0-cec9-78b5-be5a-e0e5d237ba7d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementClassOfStockAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:to="loc_us-gaap_StatementClassOfStockAxis_019d87c0-cec9-78b5-be5a-e0e5d237ba7d" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-78b5-be5a-e0e5d237ba7d_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019d87c0-cec9-78b5-be5a-e0e5d237ba7d" xlink:to="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-78b5-be5a-e0e5d237ba7d_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-76cd-9c53-44a080ff24d9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ClassOfStockDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementClassOfStockAxis_019d87c0-cec9-78b5-be5a-e0e5d237ba7d" xlink:to="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-76cd-9c53-44a080ff24d9" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockMember_019d87c0-cec9-7514-88a5-5e4e97021f12" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-76cd-9c53-44a080ff24d9" xlink:to="loc_us-gaap_CommonStockMember_019d87c0-cec9-7514-88a5-5e4e97021f12" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SeriesAConvertiblePreferredStockMember_019d87c0-cec9-7238-a87d-f48652817e67" xlink:href="rytm-20260331.xsd#rytm_SeriesAConvertiblePreferredStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockDomain_019d87c0-cec9-76cd-9c53-44a080ff24d9" xlink:to="loc_rytm_SeriesAConvertiblePreferredStockMember_019d87c0-cec9-7238-a87d-f48652817e67" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SubsidiarySaleOfStockAxis_019d87c1-69c0-764f-ba31-962188bfaf21" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SubsidiarySaleOfStockAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:to="loc_us-gaap_SubsidiarySaleOfStockAxis_019d87c1-69c0-764f-ba31-962188bfaf21" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-764f-ba31-962188bfaf21_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SaleOfStockNameOfTransactionDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_SubsidiarySaleOfStockAxis_019d87c1-69c0-764f-ba31-962188bfaf21" xlink:to="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-764f-ba31-962188bfaf21_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-7b00-98de-1f7120515139" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SaleOfStockNameOfTransactionDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_SubsidiarySaleOfStockAxis_019d87c1-69c0-764f-ba31-962188bfaf21" xlink:to="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-7b00-98de-1f7120515139" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_FollowOnOfferingMember_019d87c1-69c0-75df-bafd-37e5e0b68a2d" xlink:href="rytm-20260331.xsd#rytm_FollowOnOfferingMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-7b00-98de-1f7120515139" xlink:to="loc_rytm_FollowOnOfferingMember_019d87c1-69c0-75df-bafd-37e5e0b68a2d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OverAllotmentOptionMember_019d87c1-69c0-7a38-acfe-601a70f9f024" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OverAllotmentOptionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-7b00-98de-1f7120515139" xlink:to="loc_us-gaap_OverAllotmentOptionMember_019d87c1-69c0-7a38-acfe-601a70f9f024" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AtMarketOfferingsMember_019d87c4-5c64-784d-bf4d-f46b84d5a1aa" xlink:href="rytm-20260331.xsd#rytm_AtMarketOfferingsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SaleOfStockNameOfTransactionDomain_019d87c1-69c0-7b00-98de-1f7120515139" xlink:to="loc_rytm_AtMarketOfferingsMember_019d87c4-5c64-784d-bf4d-f46b84d5a1aa" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeAxis_019d87c4-5c64-71b5-ba13-ea19640d21b6" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:to="loc_srt_RangeAxis_019d87c4-5c64-71b5-ba13-ea19640d21b6" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeMember_019d87c4-5c64-71b5-ba13-ea19640d21b6_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_RangeAxis_019d87c4-5c64-71b5-ba13-ea19640d21b6" xlink:to="loc_srt_RangeMember_019d87c4-5c64-71b5-ba13-ea19640d21b6_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeMember_019d87c4-5c64-7944-aff2-30129923f206" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_RangeAxis_019d87c4-5c64-71b5-ba13-ea19640d21b6" xlink:to="loc_srt_RangeMember_019d87c4-5c64-7944-aff2-30129923f206" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_MaximumMember_019d87c4-5c64-75ff-87e9-4f8c68dd29bb" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_MaximumMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_RangeMember_019d87c4-5c64-7944-aff2-30129923f206" xlink:to="loc_srt_MaximumMember_019d87c4-5c64-75ff-87e9-4f8c68dd29bb" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AwardTypeAxis_019d87c4-9e28-7ddb-a565-65ec21c3c0ce" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AwardTypeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfStockByClassTable_019b7fad-591b-7038-b6b0-e289b59312e7" xlink:to="loc_us-gaap_AwardTypeAxis_019d87c4-9e28-7ddb-a565-65ec21c3c0ce" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7ddb-a565-65ec21c3c0ce_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_AwardTypeAxis_019d87c4-9e28-7ddb-a565-65ec21c3c0ce" xlink:to="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7ddb-a565-65ec21c3c0ce_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7fba-ac7a-cabbfa379138" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_AwardTypeAxis_019d87c4-9e28-7ddb-a565-65ec21c3c0ce" xlink:to="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7fba-ac7a-cabbfa379138" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EmployeeStockOptionMember_019d87c4-9e28-7ee3-bcb0-781af3bed537" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmployeeStockOptionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7fba-ac7a-cabbfa379138" xlink:to="loc_us-gaap_EmployeeStockOptionMember_019d87c4-9e28-7ee3-bcb0-781af3bed537" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RestrictedStockUnitsRSUMember_019d87c4-9e28-75cb-8378-0f06ab4a7ef3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedStockUnitsRSUMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_019d87c4-9e28-7fba-ac7a-cabbfa379138" xlink:to="loc_us-gaap_RestrictedStockUnitsRSUMember_019d87c4-9e28-75cb-8378-0f06ab4a7ef3" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockCapitalSharesReservedForFutureIssuance_019d87c0-cec9-7f1a-9d6d-180394651359" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_CommonStockCapitalSharesReservedForFutureIssuance_019d87c0-cec9-7f1a-9d6d-180394651359" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant_019d87c0-cec9-73c8-aceb-5fdf2d403399" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant_019d87c0-cec9-73c8-aceb-5fdf2d403399" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues_019d87c0-cec9-7bb6-a9a4-adf4e8c002ac" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_rytm_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues_019d87c0-cec9-7bb6-a9a4-adf4e8c002ac" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019d87c0-cec9-7b68-a562-f81841b572f9" xlink:href="rytm-20260331.xsd#rytm_TemporaryEquitySharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_rytm_TemporaryEquitySharesConversionOfConvertibleSecurities_019d87c0-cec9-7b68-a562-f81841b572f9" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019d87c0-cec9-7b18-8507-5a0edf5bbeeb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities_019d87c0-cec9-7b18-8507-5a0edf5bbeeb" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_NumberOfSharesToBeIssued_019d87c1-69c0-7e3e-a72e-2186beca1aff" xlink:href="rytm-20260331.xsd#rytm_NumberOfSharesToBeIssued"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_rytm_NumberOfSharesToBeIssued_019d87c1-69c0-7e3e-a72e-2186beca1aff" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SharesIssuedPricePerShare_019d87c1-69c0-7be8-b834-ae9259236cf5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SharesIssuedPricePerShare"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_SharesIssuedPricePerShare_019d87c1-69c0-7be8-b834-ae9259236cf5" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_NumberOfDaysToExerciseUnderwritingOption_019d87c1-69c0-7440-9b01-f15a295f0b18" xlink:href="rytm-20260331.xsd#rytm_NumberOfDaysToExerciseUnderwritingOption"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_rytm_NumberOfDaysToExerciseUnderwritingOption_019d87c1-69c0-7440-9b01-f15a295f0b18" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProceedsFromIssuanceOfCommonStock_019d87c1-69c0-7890-b269-8ddc27d15ecd" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_ProceedsFromIssuanceOfCommonStock_019d87c1-69c0-7890-b269-8ddc27d15ecd" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PaymentsForUnderwritingExpense_019d87c1-69c0-7122-9d5b-e136c195fe96" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsForUnderwritingExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_PaymentsForUnderwritingExpense_019d87c1-69c0-7122-9d5b-e136c195fe96" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SaleOfStockConsiderationReceivedOnTransaction_019d87c4-5c64-7638-a5d5-9c3a06639a90" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SaleOfStockConsiderationReceivedOnTransaction"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_SaleOfStockConsiderationReceivedOnTransaction_019d87c4-5c64-7638-a5d5-9c3a06639a90" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodSharesNewIssues_019d87c4-5c64-718d-ba00-416328e7bdb3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_StockIssuedDuringPeriodSharesNewIssues_019d87c4-5c64-718d-ba00-416328e7bdb3" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019d87c4-5c64-779d-950b-31c5a673af9f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_StockIssuedDuringPeriodValueNewIssues_019d87c4-5c64-779d-950b-31c5a673af9f" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_019d87c4-9e28-777b-8dcd-6c12cd8b2da3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_019d87c4-9e28-777b-8dcd-6c12cd8b2da3" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod_019d87c4-9e28-7615-88f2-0083e39d72ff" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ClassOfStockLineItems_019d87c0-cec9-72f7-b97f-1a4db6700388" xlink:to="loc_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod_019d87c4-9e28-7615-88f2-0083e39d72ff" xlink:type="arc" order="14"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SignificantAgreementsDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SignificantAgreementsDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SignificantAgreementsDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable_019b7fad-591b-73c9-828f-aa66190785ff" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable_019b7fad-591b-73c9-828f-aa66190785ff" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TypeOfArrangementAxis_019d30a1-5396-7d85-b726-8385476c00e5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TypeOfArrangementAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable_019b7fad-591b-73c9-828f-aa66190785ff" xlink:to="loc_us-gaap_TypeOfArrangementAxis_019d30a1-5396-7d85-b726-8385476c00e5" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d30a1-5396-7d85-b726-8385476c00e5_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_TypeOfArrangementAxis_019d30a1-5396-7d85-b726-8385476c00e5" xlink:to="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d30a1-5396-7d85-b726-8385476c00e5_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d30a1-5396-7cde-aa8e-5f898be41e85" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_TypeOfArrangementAxis_019d30a1-5396-7d85-b726-8385476c00e5" xlink:to="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d30a1-5396-7cde-aa8e-5f898be41e85" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_TerminationAgreementMember_019d30a1-5396-768d-abd5-1143259ca626" xlink:href="rytm-20260331.xsd#rytm_TerminationAgreementMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_ArrangementsAndNonarrangementTransactionsMember_019d30a1-5396-7cde-aa8e-5f898be41e85" xlink:to="loc_rytm_TerminationAgreementMember_019d30a1-5396-768d-abd5-1143259ca626" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_RepaymentOfUpfrontFeesOnTermination_019d30a1-5396-75d7-ac22-fe82b8f85437" xlink:href="rytm-20260331.xsd#rytm_RepaymentOfUpfrontFeesOnTermination"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_rytm_RepaymentOfUpfrontFeesOnTermination_019d30a1-5396-75d7-ac22-fe82b8f85437" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AdditionalConsiderationForShareRepurchase_019d30a1-5396-7f85-bf79-ef31b8c3cef1" xlink:href="rytm-20260331.xsd#rytm_AdditionalConsiderationForShareRepurchase"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_rytm_AdditionalConsiderationForShareRepurchase_019d30a1-5396-7f85-bf79-ef31b8c3cef1" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DeferredRevenueCurrent_019d30a1-5396-7787-acd9-0c8eef887002" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredRevenueCurrent"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_us-gaap_DeferredRevenueCurrent_019d30a1-5396-7787-acd9-0c8eef887002" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ReversalOfLicenseRevenueRecognizedOnTerminationOfContract_019d30a1-5396-75bf-a9f5-050e86a27e16" xlink:href="rytm-20260331.xsd#rytm_ReversalOfLicenseRevenueRecognizedOnTerminationOfContract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_rytm_ReversalOfLicenseRevenueRecognizedOnTerminationOfContract_019d30a1-5396-75bf-a9f5-050e86a27e16" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_NetReductionInLicenseRevenueUponTerminationOfContract_019d30a1-5396-798d-99d2-479251770db9" xlink:href="rytm-20260331.xsd#rytm_NetReductionInLicenseRevenueUponTerminationOfContract"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems_019d30a1-5396-7585-a0b3-e6ba4f8020d1" xlink:to="loc_rytm_NetReductionInLicenseRevenueUponTerminationOfContract_019d30a1-5396-798d-99d2-479251770db9" xlink:type="arc" order="4"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/LongTermObligationsDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#LongTermObligationsDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/LongTermObligationsDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentTable_019b7fad-591b-745c-8a9a-59a9db09b319" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_DebtInstrumentTable_019b7fad-591b-745c-8a9a-59a9db09b319" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentAxis_019b7fad-591b-7ede-8977-dcd331b15d40" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_DebtInstrumentTable_019b7fad-591b-745c-8a9a-59a9db09b319" xlink:to="loc_us-gaap_DebtInstrumentAxis_019b7fad-591b-7ede-8977-dcd331b15d40" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7ede-8977-dcd331b15d40_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_DebtInstrumentAxis_019b7fad-591b-7ede-8977-dcd331b15d40" xlink:to="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7ede-8977-dcd331b15d40_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7710-8564-3f0df0eebebe" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentNameDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_DebtInstrumentAxis_019b7fad-591b-7ede-8977-dcd331b15d40" xlink:to="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7710-8564-3f0df0eebebe" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_RevenueInterestFinancingAgreementMember_019b7fad-591b-78c2-a178-aac95861ff8e" xlink:href="rytm-20260331.xsd#rytm_RevenueInterestFinancingAgreementMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7710-8564-3f0df0eebebe" xlink:to="loc_rytm_RevenueInterestFinancingAgreementMember_019b7fad-591b-78c2-a178-aac95861ff8e" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_RoyaltyInterestFinancingAgreementMember_019b7fad-591b-7aee-afdf-7a7bc4d88413" xlink:href="rytm-20260331.xsd#rytm_RoyaltyInterestFinancingAgreementMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentNameDomain_019b7fad-591b-7710-8564-3f0df0eebebe" xlink:to="loc_rytm_RoyaltyInterestFinancingAgreementMember_019b7fad-591b-7aee-afdf-7a7bc4d88413" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeAxis_019b7fad-591b-781c-9637-df3feb6783cc" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_DebtInstrumentTable_019b7fad-591b-745c-8a9a-59a9db09b319" xlink:to="loc_srt_RangeAxis_019b7fad-591b-781c-9637-df3feb6783cc" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeMember_019b7fad-591b-781c-9637-df3feb6783cc_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_RangeAxis_019b7fad-591b-781c-9637-df3feb6783cc" xlink:to="loc_srt_RangeMember_019b7fad-591b-781c-9637-df3feb6783cc_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_RangeMember_019b7fad-591b-75c6-b6e2-321ab500e6d6" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_RangeMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_RangeAxis_019b7fad-591b-781c-9637-df3feb6783cc" xlink:to="loc_srt_RangeMember_019b7fad-591b-75c6-b6e2-321ab500e6d6" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_MinimumMember_019b7fad-591b-77e8-8ae9-2a646ecf5395" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_MinimumMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_RangeMember_019b7fad-591b-75c6-b6e2-321ab500e6d6" xlink:to="loc_srt_MinimumMember_019b7fad-591b-77e8-8ae9-2a646ecf5395" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_MaximumMember_019b7fad-591b-7ca6-ae92-ba8a50dae8e0" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_MaximumMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_RangeMember_019b7fad-591b-75c6-b6e2-321ab500e6d6" xlink:to="loc_srt_MaximumMember_019b7fad-591b-7ca6-ae92-ba8a50dae8e0" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_DebtCovenantMilestoneAxis_019db0fc-bbc9-754f-9af3-56c087018466" xlink:href="rytm-20260331.xsd#rytm_DebtCovenantMilestoneAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_DebtInstrumentTable_019b7fad-591b-745c-8a9a-59a9db09b319" xlink:to="loc_rytm_DebtCovenantMilestoneAxis_019db0fc-bbc9-754f-9af3-56c087018466" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-754f-9af3-56c087018466_default" xlink:href="rytm-20260331.xsd#rytm_DebtCovenantMilestoneDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_rytm_DebtCovenantMilestoneAxis_019db0fc-bbc9-754f-9af3-56c087018466" xlink:to="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-754f-9af3-56c087018466_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:href="rytm-20260331.xsd#rytm_DebtCovenantMilestoneDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_rytm_DebtCovenantMilestoneAxis_019db0fc-bbc9-754f-9af3-56c087018466" xlink:to="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AnnualNetRevenuesUpTo125MillionMember_019b7fad-591b-7459-8382-ffd7f5448983" xlink:href="rytm-20260331.xsd#rytm_AnnualNetRevenuesUpTo125MillionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:to="loc_rytm_AnnualNetRevenuesUpTo125MillionMember_019b7fad-591b-7459-8382-ffd7f5448983" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AnnualNetRevenuesBetween125MillionAnd300MillionMember_019b7fad-591b-7000-a05e-6da8f064d6e7" xlink:href="rytm-20260331.xsd#rytm_AnnualNetRevenuesBetween125MillionAnd300MillionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:to="loc_rytm_AnnualNetRevenuesBetween125MillionAnd300MillionMember_019b7fad-591b-7000-a05e-6da8f064d6e7" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_AnnualNetRevenuesExceeding300MillionMember_019b7fad-591b-7f27-a33a-5e7e6fcfe8e5" xlink:href="rytm-20260331.xsd#rytm_AnnualNetRevenuesExceeding300MillionMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:to="loc_rytm_AnnualNetRevenuesExceeding300MillionMember_019b7fad-591b-7f27-a33a-5e7e6fcfe8e5" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312027Member_019b7fad-591b-73d7-a27e-d055f1bf345b" xlink:href="rytm-20260331.xsd#rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312027Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:to="loc_rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312027Member_019b7fad-591b-73d7-a27e-d055f1bf345b" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312029Member_019b7fad-591b-7b0f-8732-a01077844235" xlink:href="rytm-20260331.xsd#rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312029Member"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_rytm_DebtCovenantMilestoneDomain_019db0fc-bbc9-7318-b742-06a3e5620e70" xlink:to="loc_rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312029Member_019b7fad-591b-7b0f-8732-a01077844235" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentFaceAmount_019b7fad-591b-772e-bc20-0db42d0855b9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentFaceAmount"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_DebtInstrumentFaceAmount_019b7fad-591b-772e-bc20-0db42d0855b9" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ProceedsFromRoyaltyFinancingAgreement_019b7fad-591b-7156-b54e-f4a12fc74de6" xlink:href="rytm-20260331.xsd#rytm_ProceedsFromRoyaltyFinancingAgreement"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_ProceedsFromRoyaltyFinancingAgreement_019b7fad-591b-7156-b54e-f4a12fc74de6" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_PercentOfRoyaltyInterestPaymentOnAnnualNetRevenues_019b7fad-591b-7d54-a166-5fd785497ed5" xlink:href="rytm-20260331.xsd#rytm_PercentOfRoyaltyInterestPaymentOnAnnualNetRevenues"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_PercentOfRoyaltyInterestPaymentOnAnnualNetRevenues_019b7fad-591b-7d54-a166-5fd785497ed5" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ThresholdAnnualNetRevenuesForRoyaltyInterest_019b7fad-591b-72d3-950c-bf7f315d40f7" xlink:href="rytm-20260331.xsd#rytm_ThresholdAnnualNetRevenuesForRoyaltyInterest"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_ThresholdAnnualNetRevenuesForRoyaltyInterest_019b7fad-591b-72d3-950c-bf7f315d40f7" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_ThresholdPercentOfCumulativeMinimumPaymentsFundingToInvestors_019b7fad-591b-7705-b613-53b6a9af6ec8" xlink:href="rytm-20260331.xsd#rytm_ThresholdPercentOfCumulativeMinimumPaymentsFundingToInvestors"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_ThresholdPercentOfCumulativeMinimumPaymentsFundingToInvestors_019b7fad-591b-7705-b613-53b6a9af6ec8" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RepaymentsOfLongTermDebtAndCapitalSecurities_019b7fad-591b-71f8-b217-0aae3829e20a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RepaymentsOfLongTermDebtAndCapitalSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_RepaymentsOfLongTermDebtAndCapitalSecurities_019b7fad-591b-71f8-b217-0aae3829e20a" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProceedsFromRepaymentsOfLongTermDebtAndCapitalSecurities_019b7fad-591b-76b1-a9cb-bb4323394d8e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProceedsFromRepaymentsOfLongTermDebtAndCapitalSecurities"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_ProceedsFromRepaymentsOfLongTermDebtAndCapitalSecurities_019b7fad-591b-76b1-a9cb-bb4323394d8e" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_RevenueInterestsPayableCapAsPercentOfInvestmentAmount_019b7fad-591b-757d-aec2-12fbedca5a58" xlink:href="rytm-20260331.xsd#rytm_RevenueInterestsPayableCapAsPercentOfInvestmentAmount"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_RevenueInterestsPayableCapAsPercentOfInvestmentAmount_019b7fad-591b-757d-aec2-12fbedca5a58" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_RevenueInterestPaymentPeriodFromInitialClosing_019b7fad-591b-7dc1-a43a-ea49573471ec" xlink:href="rytm-20260331.xsd#rytm_RevenueInterestPaymentPeriodFromInitialClosing"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_rytm_RevenueInterestPaymentPeriodFromInitialClosing_019b7fad-591b-7dc1-a43a-ea49573471ec" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EmbeddedDerivativeFairValueOfEmbeddedDerivativeNet_019b7fad-591b-7f5b-b381-2957d3e254d1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmbeddedDerivativeFairValueOfEmbeddedDerivativeNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_EmbeddedDerivativeFairValueOfEmbeddedDerivativeNet_019b7fad-591b-7f5b-b381-2957d3e254d1" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EmbeddedDerivativeGainLossOnEmbeddedDerivativeNet_019b7fad-591b-7779-9a63-12c3e5767f44" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmbeddedDerivativeGainLossOnEmbeddedDerivativeNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_EmbeddedDerivativeGainLossOnEmbeddedDerivativeNet_019b7fad-591b-7779-9a63-12c3e5767f44" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DeferredRevenueNoncurrent_019b7fad-591b-7379-8085-4331bf6c95ae" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredRevenueNoncurrent"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_DeferredRevenueNoncurrent_019b7fad-591b-7379-8085-4331bf6c95ae" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DebtInstrumentInterestRateEffectivePercentage_019b7fad-591b-7815-9d32-e3b019d2c0e7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DebtInstrumentInterestRateEffectivePercentage"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_DebtInstrumentInterestRateEffectivePercentage_019b7fad-591b-7815-9d32-e3b019d2c0e7" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DeferredFinanceCostsNet_019b7fad-591b-7507-99b0-aa5aef548eed" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredFinanceCostsNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_DebtInstrumentLineItems_019b7fad-591b-787e-83ab-b0d346a96047" xlink:to="loc_us-gaap_DeferredFinanceCostsNet_019b7fad-591b-7507-99b0-aa5aef548eed" xlink:type="arc" order="13"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SegmentandGeographicInformationProfitlossDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SegmentandGeographicInformationProfitlossDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SegmentandGeographicInformationProfitlossDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SegmentReportingInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-70d7-9405-48477be137b4" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-70d7-9405-48477be137b4" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementBusinessSegmentsAxis_019b7fad-591b-76e4-aac0-0e3a33b09434" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StatementBusinessSegmentsAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-70d7-9405-48477be137b4" xlink:to="loc_us-gaap_StatementBusinessSegmentsAxis_019b7fad-591b-76e4-aac0-0e3a33b09434" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SegmentDomain_019b7fad-591b-76e4-aac0-0e3a33b09434_default" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SegmentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementBusinessSegmentsAxis_019b7fad-591b-76e4-aac0-0e3a33b09434" xlink:to="loc_us-gaap_SegmentDomain_019b7fad-591b-76e4-aac0-0e3a33b09434_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SegmentDomain_019b7fad-591b-7de0-97e7-47ba29b4dfec" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SegmentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementBusinessSegmentsAxis_019b7fad-591b-76e4-aac0-0e3a33b09434" xlink:to="loc_us-gaap_SegmentDomain_019b7fad-591b-7de0-97e7-47ba29b4dfec" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_SingleReportableSegmentMember_019b7fad-591b-71a1-8488-a065820b7ef0" xlink:href="rytm-20260331.xsd#rytm_SingleReportableSegmentMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentDomain_019b7fad-591b-7de0-97e7-47ba29b4dfec" xlink:to="loc_rytm_SingleReportableSegmentMember_019b7fad-591b-71a1-8488-a065820b7ef0" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_StatementGeographicalAxis_019b7fad-591b-73a7-9230-9e5b689ee0dd" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_StatementGeographicalAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-70d7-9405-48477be137b4" xlink:to="loc_srt_StatementGeographicalAxis_019b7fad-591b-73a7-9230-9e5b689ee0dd" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_SegmentGeographicalDomain_019b7fad-591b-73a7-9230-9e5b689ee0dd_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_SegmentGeographicalDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_StatementGeographicalAxis_019b7fad-591b-73a7-9230-9e5b689ee0dd" xlink:to="loc_srt_SegmentGeographicalDomain_019b7fad-591b-73a7-9230-9e5b689ee0dd_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7f86-a5de-a8cabbb9f36f" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_SegmentGeographicalDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_StatementGeographicalAxis_019b7fad-591b-73a7-9230-9e5b689ee0dd" xlink:to="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7f86-a5de-a8cabbb9f36f" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_country_US_019b7fad-591b-70b3-a23d-00b7b2fafa8d" xlink:href="https://xbrl.sec.gov/country/2025/country-2025.xsd#country_US"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7f86-a5de-a8cabbb9f36f" xlink:to="loc_country_US_019b7fad-591b-70b3-a23d-00b7b2fafa8d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonUsMember_019b7fad-591b-741d-bb76-eb5f34bcea31" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonUsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7f86-a5de-a8cabbb9f36f" xlink:to="loc_us-gaap_NonUsMember_019b7fad-591b-741d-bb76-eb5f34bcea31" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductOrServiceAxis_019b7fad-591b-7e05-a185-5b279cfb23d3" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductOrServiceAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-70d7-9405-48477be137b4" xlink:to="loc_srt_ProductOrServiceAxis_019b7fad-591b-7e05-a185-5b279cfb23d3" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7e05-a185-5b279cfb23d3_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_ProductOrServiceAxis_019b7fad-591b-7e05-a185-5b279cfb23d3" xlink:to="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7e05-a185-5b279cfb23d3_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7717-a28e-d7059a3f4829" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_ProductsAndServicesDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_ProductOrServiceAxis_019b7fad-591b-7e05-a185-5b279cfb23d3" xlink:to="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7717-a28e-d7059a3f4829" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProductMember_019b7fad-591b-7abb-8fb0-5f29e9e7cd1e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProductMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7717-a28e-d7059a3f4829" xlink:to="loc_us-gaap_ProductMember_019b7fad-591b-7abb-8fb0-5f29e9e7cd1e" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LicenseMember_019b7fad-591b-7d4b-908f-79c5dcb2c395" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LicenseMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_ProductsAndServicesDomain_019b7fad-591b-7717-a28e-d7059a3f4829" xlink:to="loc_us-gaap_LicenseMember_019b7fad-591b-7d4b-908f-79c5dcb2c395" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-591b-741a-aa5f-528b76ce5323" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-591b-741a-aa5f-528b76ce5323" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostOfGoodsAndServicesSold_019b7fad-591b-7b72-94ad-b76e88812256" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostOfGoodsAndServicesSold"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_CostOfGoodsAndServicesSold_019b7fad-591b-7b72-94ad-b76e88812256" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LaborAndRelatedExpense_019b7fad-591b-7ad6-9998-8294315ee8a1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LaborAndRelatedExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_LaborAndRelatedExpense_019b7fad-591b-7ad6-9998-8294315ee8a1" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_PreclinicalClinicalAndDevelopmentExpense_019b7fad-591b-7199-b609-c858c5c64ef5" xlink:href="rytm-20260331.xsd#rytm_PreclinicalClinicalAndDevelopmentExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_rytm_PreclinicalClinicalAndDevelopmentExpense_019b7fad-591b-7199-b609-c858c5c64ef5" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_rytm_CommercialAndMedicalExpenses_019b7fad-591b-76f0-9937-9f001eefcfe0" xlink:href="rytm-20260331.xsd#rytm_CommercialAndMedicalExpenses"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_rytm_CommercialAndMedicalExpenses_019b7fad-591b-76f0-9937-9f001eefcfe0" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_GeneralAndAdministrativeExpense_019b7fad-591b-7fdd-b162-2cb8e8f945be" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_GeneralAndAdministrativeExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_GeneralAndAdministrativeExpense_019b7fad-591b-7fdd-b162-2cb8e8f945be" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherNonoperatingIncomeExpense_019db0e5-85d5-7aac-ba76-fe17dbe2f7db" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherNonoperatingIncomeExpense"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_OtherNonoperatingIncomeExpense_019db0e5-85d5-7aac-ba76-fe17dbe2f7db" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_InterestIncomeExpenseNonoperatingNet_019b7fad-591b-7cdd-aaf6-ee78aad45721" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InterestIncomeExpenseNonoperatingNet"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_InterestIncomeExpenseNonoperatingNet_019b7fad-591b-7cdd-aaf6-ee78aad45721" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit_019db0e6-0f8d-7745-b6b3-5030117b2604" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeTaxExpenseBenefit"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_IncomeTaxExpenseBenefit_019db0e6-0f8d-7745-b6b3-5030117b2604" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLoss_019b7fad-591b-7381-9140-2bca6f9243b8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-782b-b5ef-5541efeb9ecb" xlink:to="loc_us-gaap_NetIncomeLoss_019b7fad-591b-7381-9140-2bca6f9243b8" xlink:type="arc" order="9"/>
  </link:definitionLink>
  <link:roleRef roleURI="http://www.rhythmtx.com/role/SegmentandGeographicInformationRevenuesDetails" xlink:type="simple" xlink:href="rytm-20260331.xsd#SegmentandGeographicInformationRevenuesDetails"/>
  <link:definitionLink xlink:role="http://www.rhythmtx.com/role/SegmentandGeographicInformationRevenuesDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-79fa-91e8-7f299b58a15d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SegmentReportingInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-7544-a122-c233b4497195" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-79fa-91e8-7f299b58a15d" xlink:to="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-7544-a122-c233b4497195" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_StatementGeographicalAxis_019b7fad-591b-7ed3-af09-53ecb258e017" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_StatementGeographicalAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable_019b7fad-591b-7544-a122-c233b4497195" xlink:to="loc_srt_StatementGeographicalAxis_019b7fad-591b-7ed3-af09-53ecb258e017" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7ed3-af09-53ecb258e017_default" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_SegmentGeographicalDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_srt_StatementGeographicalAxis_019b7fad-591b-7ed3-af09-53ecb258e017" xlink:to="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7ed3-af09-53ecb258e017_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7595-9755-af2cd14b1ea7" xlink:href="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd#srt_SegmentGeographicalDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_srt_StatementGeographicalAxis_019b7fad-591b-7ed3-af09-53ecb258e017" xlink:to="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7595-9755-af2cd14b1ea7" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_country_US_019b7fad-591b-7953-b9e6-3f77607beb42" xlink:href="https://xbrl.sec.gov/country/2025/country-2025.xsd#country_US"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7595-9755-af2cd14b1ea7" xlink:to="loc_country_US_019b7fad-591b-7953-b9e6-3f77607beb42" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonUsMember_019b7fad-591b-71f1-950e-7751eb893650" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonUsMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_srt_SegmentGeographicalDomain_019b7fad-591b-7595-9755-af2cd14b1ea7" xlink:to="loc_us-gaap_NonUsMember_019b7fad-591b-71f1-950e-7751eb893650" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-591b-7f13-b207-b80cc30d96fb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_SegmentReportingInformationLineItems_019b7fad-591b-79fa-91e8-7f299b58a15d" xlink:to="loc_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_019b7fad-591b-7f13-b207-b80cc30d96fb" xlink:type="arc" order="0"/>
  </link:definitionLink>
</link:linkbase>
