This article addresses behavioral and social research priorities for prevention and treatment of HIV-1 infection. The approach used to define these priorities is based on 3 premises: (1) Behavioral interventions for prevention and treatment are necessary but not sufficient for producing reductions in transmission or advances in treatment; the same is true of biomedical interventions, and by themselves, they cannot maximally impact the health of communities. (2) Combination prevention and treatment strategies should include optimal combinations of behavioral and biomedical strategies but also must include the varieties of the behaviors of individuals, communities, and systems needed to ensure effective treatment and prevention. (3) And it is no longer useful, given scientific advances in understanding how treatment contributes to prevention, to discuss prevention without incorporating treatment and vice versa. This redefinition of behavioral approaches in combination prevention and treatment provides a new paradigm for defining behavioral research in HIV-1 disease. No longer is it sufficient to focus on single behavior (eg, high-risk sexual behavior, adherence to antiretroviral medications) of individuals in a vertical way. Rather, the behavioral agenda not only need to expand to encompass traditional investigations of single behaviors but also need to include the behavior of many actors and systems that are essential in facilitating reductions in transmission and improvements in treatment outcomes. In addition, there is the need for expanded implementation research agenda to encompass the study of methods to achieve high coverage, acceptability, and effectiveness of available menu of interventions.