The past 30 years of research on the epidemiology of drug use, drug use disorders, and related conditions, such as HIV, has provided major insight into these conditions. Drug use peaked in the late 1970s, decreased across the 1980s, increased in the 1990s, and has remained stable during the past few years. Within this broad pattern, specific epidemics of crack cocaine, amphetamines, club drugs (such as Ecstasy), heroin, and prescription opioids and associated epidemics of HIV and other infectious diseases have been identified and tracked. Besides major accomplishments in surveillance, the epidemiology of drug use and drug use disorders has traditionally focused on identifying risk factors at the individual (genetic factors, high-risk behaviors), family (child abuse), neighborhood (high availability of drugs), and societal (policies and laws) levels as domains of influence, not as components of interrelated processes. Research includes careful cross-sectional and longitudinal observational studies as well as clinical epidemiological experiments in which prevention interventions test specific etiological theories. Building on this background, the next challenges for the epidemiology of drug use and drug use disorders will be to link individual vulnerabilities with specific environmental factors by using multilevel methodological approaches. For example, what are the environmental factors that interact with individual vulnerabilities to produce drug addictions and drug consequences such as HIV? Research in genetic epidemiology has demonstrated the potential for studies of interactions of genetic and environmental factors. The field needs to focus on linking science with epidemiology to make progress in understanding these complex health conditions.