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  <xsd:import namespace="http://www.xbrl.org/2009/role/negated" schemaLocation="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd" />
  <xsd:import namespace="http://www.xbrl.org/dtr/type/2022-03-31" schemaLocation="https://www.xbrl.org/dtr/type/2022-03-31/types.xsd" />
  <xsd:import namespace="http://www.xbrl.org/2003/instance" schemaLocation="http://www.xbrl.org/2003/xbrl-instance-2003-12-31.xsd" />
  <xsd:import namespace="http://xbrl.org/2005/xbrldt" schemaLocation="http://www.xbrl.org/2005/xbrldt-2005.xsd" />
  <xsd:import namespace="http://fasb.org/us-roles/2023" schemaLocation="https://xbrl.fasb.org/us-gaap/2023/elts/us-roles-2023.xsd" />
  <xsd:import namespace="http://fasb.org/us-gaap/2023" schemaLocation="https://xbrl.fasb.org/us-gaap/2023/elts/us-gaap-2023.xsd" />
  <xsd:import namespace="http://fasb.org/srt/2023" schemaLocation="https://xbrl.fasb.org/srt/2023/elts/srt-2023.xsd" />
  <xsd:element id="rytm_AccruedResearchAndDevelopmentCosts" name="AccruedResearchAndDevelopmentCosts" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" xbrli:balance="credit" />
  <xsd:element id="rytm_AccruedPayrollRelatedExpenseCurrent" name="AccruedPayrollRelatedExpenseCurrent" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" xbrli:balance="credit" />
  <xsd:element id="rytm_OffBalanceSheetRiskAndConcentrationsOfCreditRiskAbstract" name="OffBalanceSheetRiskAndConcentrationsOfCreditRiskAbstract" nillable="true" type="xbrli:stringItemType" substitutionGroup="xbrli:item" abstract="true" xbrli:periodType="duration" />
  <xsd:element id="rytm_NumberOfFederallyInsuredFinancialInstitutions" name="NumberOfFederallyInsuredFinancialInstitutions" nillable="true" type="xbrli:integerItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" />
  <xsd:element id="rytm_LicenseAgreementMember" name="LicenseAgreementMember" nillable="true" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" abstract="true" xbrli:periodType="duration" />
  <xsd:element id="rytm_AggregatePaymentUponAchievementOfDevelopmentAndCommercialMilestones" name="AggregatePaymentUponAchievementOfDevelopmentAndCommercialMilestones" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" xbrli:balance="credit" />
  <xsd:element id="rytm_TwoThousandSeventeenEmployeeStockPurchasePlanMember" name="TwoThousandSeventeenEmployeeStockPurchasePlanMember" nillable="true" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" abstract="true" xbrli:periodType="duration" />
  <xsd:element id="rytm_StockIssuedDuringPeriodSharesNewIssuesLicenseAgreement" name="StockIssuedDuringPeriodSharesNewIssuesLicenseAgreement" nillable="true" type="xbrli:sharesItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" />
  <xsd:element id="rytm_CorporateDebtSecuritiesAndCommercialPaperMember" name="CorporateDebtSecuritiesAndCommercialPaperMember" nillable="true" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" abstract="true" xbrli:periodType="duration" />
  <xsd:element id="rytm_StockIssuedDuringPeriodValueStockOptionsAndRestrictedStockUnitsVesting" name="StockIssuedDuringPeriodValueStockOptionsAndRestrictedStockUnitsVesting" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" xbrli:balance="credit" />
  <xsd:element id="rytm_StockIssuedDuringPeriodSharesStockOptionsAndRestrictedStockUnitsVesting" name="StockIssuedDuringPeriodSharesStockOptionsAndRestrictedStockUnitsVesting" nillable="true" type="xbrli:sharesItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" />
  <xsd:element id="rytm_DeferredRentExpense" name="DeferredRentExpense" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" xbrli:balance="debit" />
  <xsd:element id="rytm_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFour" name="FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFour" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" xbrli:balance="debit" />
  <xsd:element id="rytm_MilestoneObligationUnderLicenseAgreement" name="MilestoneObligationUnderLicenseAgreement" nillable="true" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" xbrli:balance="credit" />
  <xsd:element name="RareStoneGroupLtdMember" id="rytm_RareStoneGroupLtdMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="UpfrontPayment" id="rytm_UpfrontPayment" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="ImpairmentOrDisposalOfLongLivedAssetsAndPropertyPlantAndEquipmentPolicyTextBlock" id="rytm_ImpairmentOrDisposalOfLongLivedAssetsAndPropertyPlantAndEquipmentPolicyTextBlock" type="dtr-types:textBlockItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="Depreciationdepletionandamortizationpropertyandequipmentincludingintangibleassets" id="rytm_Depreciationdepletionandamortizationpropertyandequipmentincludingintangibleassets" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="CostOfProductSalesPolicyTextBlock" id="rytm_CostOfProductSalesPolicyTextBlock" type="dtr-types:textBlockItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="AtMarketOfferingsMember" id="rytm_AtMarketOfferingsMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="EmploymentInducementPlan2022Member" id="rytm_EmploymentInducementPlan2022Member" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="RoyaltiesCurrent" id="rytm_RoyaltiesCurrent" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="instant" abstract="false" xbrli:balance="credit" />
  <xsd:element name="RarestoneValuationUnrealizedGainLoss" id="rytm_RarestoneValuationUnrealizedGainLoss" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="DeferredFinancingCostsIncludedInAccruedExpenses" id="rytm_DeferredFinancingCostsIncludedInAccruedExpenses" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="credit" />
  <xsd:element name="LicenseAgreementNumberOfPerformanceObligations" id="rytm_LicenseAgreementNumberOfPerformanceObligations" type="xbrli:integerItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="LicenseAgreementCommercialManufacturingSupplyDiscount" id="rytm_LicenseAgreementCommercialManufacturingSupplyDiscount" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="LicenseAgreementsAccountingPolicyPolicyTextBlock" id="rytm_LicenseAgreementsAccountingPolicyPolicyTextBlock" type="dtr-types:textBlockItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="DeferredRoyaltyObligationAccountingPolicyPolicyTextBlock" id="rytm_DeferredRoyaltyObligationAccountingPolicyPolicyTextBlock" type="dtr-types:textBlockItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="LicenseAgreementUpfrontConsideration" id="rytm_LicenseAgreementUpfrontConsideration" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="RevenueInterestFinancingAgreementMember" id="rytm_RevenueInterestFinancingAgreementMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="AnnualNetRevenuesUpTo125MillionMember" id="rytm_AnnualNetRevenuesUpTo125MillionMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="AnnualNetRevenuesBetween125MillionAnd300MillionMember" id="rytm_AnnualNetRevenuesBetween125MillionAnd300MillionMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="AnnualNetRevenuesExceeding300MillionMember" id="rytm_AnnualNetRevenuesExceeding300MillionMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="CumulativeMinimumPaymentsFundingThresholdDateMarch312027Member" id="rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312027Member" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="CumulativeMinimumPaymentsFundingThresholdDateMarch312029Member" id="rytm_CumulativeMinimumPaymentsFundingThresholdDateMarch312029Member" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="PercentOfRoyaltyInterestPaymentOnAnnualNetRevenues" id="rytm_PercentOfRoyaltyInterestPaymentOnAnnualNetRevenues" type="dtr-types:percentItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="ThresholdAnnualNetRevenuesForRoyaltyInterest" id="rytm_ThresholdAnnualNetRevenuesForRoyaltyInterest" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="credit" />
  <xsd:element name="ThresholdPercentOfCumulativeMinimumPaymentsFundingToInvestors" id="rytm_ThresholdPercentOfCumulativeMinimumPaymentsFundingToInvestors" type="dtr-types:percentItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="RevenueInterestsPayableCapAsPercentOfInvestmentAmount" id="rytm_RevenueInterestsPayableCapAsPercentOfInvestmentAmount" type="dtr-types:percentItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="RevenueInterestPaymentPeriodFromInitialClosing" id="rytm_RevenueInterestPaymentPeriodFromInitialClosing" type="xbrli:durationItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="CustomerOneMember" id="rytm_CustomerOneMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="RarestoneValuationRealizedGainLoss" id="rytm_RarestoneValuationRealizedGainLoss" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="credit" />
  <xsd:element name="NonCashInterestExpenseAndAmortizationOfDebtIssuanceCosts" id="rytm_NonCashInterestExpenseAndAmortizationOfDebtIssuanceCosts" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="SalesAllowancesAccruedCurrent" id="rytm_SalesAllowancesAccruedCurrent" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="instant" abstract="false" xbrli:balance="credit" />
  <xsd:element name="InventoryMember" id="rytm_InventoryMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="NumberOfIndependentSubStudiesInPatients" id="rytm_NumberOfIndependentSubStudiesInPatients" type="xbrli:integerItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="XinventoBVMember" id="rytm_XinventoBVMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="CommercialRegulatoryApprovalAndMilestonePayments" id="rytm_CommercialRegulatoryApprovalAndMilestonePayments" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="ClinicalDevelopmentMilestonePayments" id="rytm_ClinicalDevelopmentMilestonePayments" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="SalesMilestonePayments" id="rytm_SalesMilestonePayments" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="ProceedsFromRoyaltyFinancingAgreement" id="rytm_ProceedsFromRoyaltyFinancingAgreement" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="CapitalizedMilestonesMember" id="rytm_CapitalizedMilestonesMember" type="dtr-types:domainItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="true" />
  <xsd:element name="AcquiredFiniteLivedIntangiblesPolicyTextBlock" id="rytm_AcquiredFiniteLivedIntangiblesPolicyTextBlock" type="dtr-types:textBlockItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" />
  <xsd:element name="AcquiredInProcessResearchAndDevelopmentAssetsClassifiedAsInvestingActivities" id="rytm_AcquiredInProcessResearchAndDevelopmentAssetsClassifiedAsInvestingActivities" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="debit" />
  <xsd:element name="HoldbackPayableOnOneYearAnniversaryOfAcquisition" id="rytm_HoldbackPayableOnOneYearAnniversaryOfAcquisition" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="instant" abstract="false" xbrli:balance="credit" />
  <xsd:element name="ReclassificationOfLosses" id="rytm_ReclassificationOfLosses" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" nillable="true" xbrli:periodType="duration" abstract="false" xbrli:balance="credit" />
</xsd:schema>
