Scientists have made great discoveries concerning human physiology and gained tremendous knowledge during drug development efforts. Modeling and simulation are the tools used to integrate previously obtained knowledge to make predictions for the future that have benefited the entire drug development program. The objective of this chapter is to introduce quantitative models that are used to predict biopharmaceutical in vivo performance for orally administered drug products. Both conventional and mechanism-based pharmacokinetic (PK) models will be discussed. Specifically, quantitative prediction of absorption, distribution, metabolism, and excretion using biopharmaceutics and PK modeling and simulation will be discussed in detail. The application of modeling and simulation in both drug product development and regulatory assessment will be introduced.