Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.