Pre-exposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. Proof-of-concept that PrEP, as oral or vaginal topical tenofovir-based products, protects against sexual HIV acquisition has been demonstrated in clinical trials conducted among men who have sex with men and heterosexual men and women. The degree of HIV protection in these trials was strongly related to the level of adherence to PrEP. Many questions are yet unanswered--including how to motivate uptake of and sustain adherence to PrEP for HIV prevention, how much PrEP use is enough to achieve HIV protection, and the potential of "next-generation" PrEP agents to improve on this effective technology.