This article presents an overview of couple-based HIV prevention research to date, advantages of using and core components of couple-based interventions, gaps in the current understanding of couple-based HIV prevention, status of dissemination research and the transportability of effective couple-based HIV prevention and treatment to real-world settings, and recommendations for future directions in couple-based prevention and treatment. Couple-based studies conducted among several populations-heterosexuals, men who have sex with men, and drug users-reported in the research literature were reviewed. Commonalities and limitations were noted in customary focus areas of the couple-based approaches: sexual and drug risk reduction, HIV testing behaviors, adherence to HIV treatment, and prevention of mother-to-child transmission. Couple-based intervention strategies have been rigorously tested and are a valuable addition to the arsenal of HIV prevention strategies. Immediate needs and opportunities include couple-based intervention strategies for prevention of HIV and other sexually transmitted infections among serodiscordant couples, couples who do not know their HIV status, and couples in whom both partners are HIV negative but at risk of HIV infection. There is a particular need to develop couple-based intervention strategies for men who have sex with men and for drug-involved couples.