Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. 2008; Johnston et al. 2011; SAMHSA 2011). This paper presents a summary of the goals, methods and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12 month prevalence rates of substance dependence in U.S. adults (about 12% for alcohol and 2–3% for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of U.S. youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8% and illicit drug use disorders is 2–3% (Merikangas et al. 2010; Swendsen et al. in press, SAMSHA, 2011). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of substance use disorders. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat substance use disorders.