Reducing the incidence of HIV remains one of our greatest public health challenges. However, there is growing optimism that preexposure prophylaxis (PrEP) could have a major impact on preventing incident HIV infection. Recently presented data on the use of oral PrEP in men who have sex with men (MSM) have provided proof-of-principle for this strategy. Additional clinical trials are evaluating whether PrEP provides similar protection to risk groups other than MSM, such as heterosexual persons and injection drug users. Still unanswered questions include optimal dosing strategies, long-term safety, maximizing adherence and minimizing costs, addressing drug resistance in the face of PrEP failure, optimizing access, and assessing effects on risk behavior. Future implementation will be guided by the results of clinical trials in progress. This article provides a review of the data on the potential strengths and limitations of PrEP as an HIV prevention strategy, identifies challenges to implementation of this approach, and outlines knowledge gaps.