Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.