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Despite these advances, oligonucleotide development presents unique challenges compared with small molecules and biologics, including rapid plasma distributive clearance, nuclease\u2010mediated degradation, limited extrahepatic distribution, and prolonged pharmacodynamic effects driven by tissue retention and intracellular mechanisms such as RNA\u2010induced silencing complex loading or RNase H\u2010mediated activity. Consequently, tissue disposition and intracellular pharmacology most often govern therapeutic response more directly than plasma exposures alone, complicating conventional approaches to dose selection, efficacy prediction, and safety assessment. Model\u2010informed drug development (MIDD) offers a quantitative framework to address these challenges through integration of preclinical, translational, and clinical data into empirical, mechanistic, and systems\u2010level models. This review summarizes current and emerging MIDD applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs. Approaches discussed include empirical and semi\u2010mechanistic pharmacokinetic\/pharmacodynamic (PK\/PD) models, physiologically based pharmacokinetic (PBPK) frameworks describing tissue\u2010selective biodistribution and intracellular disposition, and quantitative systems pharmacology (QSP) models linking molecular target modulation with downstream biologic and clinical responses. Collectively, these approaches have supported cross\u2010species translation; human dose selection; clinical trial optimization; and mechanistic understanding of oligonucleotide absorption, distribution, metabolism, excretion, and pharmacology. 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