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Clinical pharmacology, modeling, and simulation\u2010based approaches can help address these challenges by informing decision\u2010making, mitigating uncertainty, and guiding optimal dose and regimen selection for the appropriate patient population. These approaches help streamline trial designs by reducing the scope and number of clinical trial evaluations, using exposure\u2013response analyses to optimize dosing, the use of mechanistic\u2010physiologically based pharmacokinetics (M\u2010PBPK)\u2010based approaches for biopharmaceutical and formulation optimization, evaluations of drug\u2013drug interactions, and organ impairment. These strategies increase development efficiency across all stages of drug development, thereby improving the probability of success. This review highlights case studies that applied innovative clinical and quantitative pharmacology approaches across early and late stages of drug development and regulatory decision\u2010making in rare diseases. 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