Thirty years into the global HIV epidemic, the need for effective prevention strategies remains critical. In July 2010, the CAPRISA-004 study demonstrated that topical administration of a gel containing the antiretroviral agent tenofovir decreased the risk of HIV acquisition among at-risk heterosexual women. Subsequently, the iPrEx study reported that prophylactic use of a daily oral tablet containing tenofovir and emtricitabine reduced the risk of HIV acquisition among high-risk men who have sex with men. These studies illustrate the promise of antiretroviral pre-exposure chemoprophylaxis (PrEP) as an innovative prevention approach. This review discusses the rationale for chemoprophylaxis, compares the advantages of topical and oral delivery, outlines recommended safety monitoring, offers principles to guide selection of antiretroviral agents, and highlights potential unintended consequences of PrEP use. If future studies confirm the safety and efficacy of tenofovir gel and oral PrEP, successful implementation of these strategies could significantly impact the HIV epidemic.