The use of antiretroviral therapy (ART) has been associated with significant improvement in morbidity and survival of persons living with HIV. In addition, recently, there has also been intense interest in the potential impact of ART on HIV transmission and consequently on the trajectory of the HIV epidemic globally. Evidence from mathematical modeling analyses and observational and ecological studies supports the potential for ART as prevention. However, definitive data from clinical trials are awaited. In the United States, the feasibility and potential of using ART as a prevention strategy presents particular challenges: the large number of individuals with undiagnosed HIV; the predominance of disenfranchised individuals affected by the epidemic; evidence of delay in engagement in HIV care after diagnosis with attendant late initiation of ART; and difficulties with consistent long-term adherence to ART and concerns regarding long-term risk-behavior change. Thus, for this novel effort to succeed, a multidimensional approach is necessary that must include policy changes, social mobilization, and improved access to clinical and supportive services for persons living with HIV, with a particular focus on the unique needs of at-risk populations, combined with engagement of all cadres of health care providers and community constituencies.