Mathematical modeling is being applied to address essential questions in drug development, such as the mechanism of action of a therapeutic agent, its pharmacology and impact on disease. The successful application of such modeling has let to the U.S. FDA’s Model-Informed Drug Development (MIDD) Pilot Program to facilitate the development and application of pharmacological, biological, and statistical models of preclinical and clinical data. The pilot program is discussing modeling that impacts important aspects of drug development including the recommendation of therapeutic regimens in special populations in the absence of dedicated clinical trials. A broad perspective is offered to highlight how such models are qualified and evaluated among research teams and with regulators, in order to meet the high bar of supporting decisions that impact public health.