The advent of preventive treatment for HIV highlights the urgent need for basic, clinical, and epidemiologic research targeting the pathogenesis and prevention of cutaneous and mucosal infection. In addition, the impact of HIV prophylaxis on the frequency of risk behaviors and antiretroviral drug resistance, especially in cities with high HIV prevalence, must be evaluated. In our view, the available data (albeit not definitive) are strong enough to support the provision of post-exposure prophylaxis in select cases of sexual and injection drug use exposure in addition to occupational exposures. However, post-exposure treatment should be used judiciously and only in the context of a comprehensive prevention program. Ultimately, primary exposure prevention, whether in health care facilities or in the community, is the most important strategy to prevent AIDS.