In this review, we discuss the importance of investigating both sex and gender differences in addiction and relapse in studies of humans and in animal models. Addiction is both a cultural and biological phenomenon. Sex and gender differences are not solely determined by our biology, nor are they entirely cultural; they are interactions between biology and the environment that are continuously played out throughout development. Lessons from the historical record illustrate how context and attitudes affect the way that substance use in men and women is regarded. Finally, cultural and environmental influences may differentially affect men and women, and affect how they respond to drugs of abuse and to treatment protocols. We recommend that both animal models and clinical research need to be developed to consider how contextual and social factors may influence the biological processes of addiction and relapse differentially in men and women.