This review presents nine case studies where physiologically based pharmacokinetic modeling has been used in the design and development of extended-release formulations. While the approaches for creating the models were similar, in each case a product-development or drug-delivery problem unique to each compound was solved so that the drug-release rate could be optimized to achieve the best clinical performance. Examples presented include understanding the relationship between colonic absorption and efflux, effect of drug release and gastric emptying on maximum achieved drug concentration in plasma and area under the plasma concentration–time curve for a Biopharmaceutics Classification System class 3 compound, feasibility of an extended-release product for a prodrug, feasibility of an extended-release product for a Biopharmaceutics Classification System class 4 compound and predicting the pharmacokinetics in humans based on a primate model and coupling the physiologically-based pharmacokinetic model with a pharmacodynamic model so that the clinical efficacy of the formulations could be predicted based on the simulated plasma concentrations. The use of physiologically based pharmacokinetic models in the development of extended-release formulations is rapidly becoming an acceptable part of the knowledge management and design space components of a quality by design approach to product development. As the use of these in silico tools increase and examples become available through scientific presentations and literature, the inclusion of this approach will become a necessary part of the development process rather than the exception.