While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated.