In the 50 years since its establishment, the National Institute on Drug Abuse has made significant investment and strides toward improving individual and public health. Epidemiology serves as the foundation for understanding the how many, why, how, where, and who of drug use and its consequences, and effective epidemiology research and training are geared toward actionable findings that can inform real-world responses. Epidemiologic findings enhance clinicians’ ability to provide ongoing care by incorporating information about the patterns and outcomes of drug use that their patients may experience. The goal of this article is to provide a context for epidemiology of substance use as a foundation for prevention, with examples of how epidemiology can provide targets for prevention, and to set the stage for addressing the importance of prevention in clinical settings.