Antiretroviral therapy (ART) has the potential to prevent human immunodeficiency virus (HIV) transmission by reducing the concentration of HIV in blood and genital secretions. Indeed, mathematical models with favorable assumptions suggest the potential of ART to stop the spread of HIV infection. Empirical results from ecological and population-based studies and from several short-term observational studies involving HIV status-discordant heterosexual couples suggest that ART reduces the rate of HIV transmission. A multinational, randomized, controlled trial (National Institutes of Health HPTN052) examining the reliability and durability of ART as prevention of transmission in HIV status-discordant couples is under way. The latter and other studies also consider sexual risk-taking behavior and transmission of HIV-resistant variants when ART is used as prevention. Early HIV detection and treatment (ie, test and treat) are being considered as an important prevention strategy. In this article, we review the data supporting the use of ART to prevent HIV transmission and critically examine the public health implications of this strategy.