Pre-exposure prophylaxis (PrEP), in which HIV-uninfected persons use oral or topical antiretroviral medications to protect against HIV acquisition, is a promising new HIV prevention strategy. The biologic rationale for evaluation of PrEP for sexual HIV prevention included nonhuman primate models and the efficacy of antiretroviral prophylaxis for HIV-exposed infants. Proof-of-concept that PrEP protects against sexual HIV acquisition has been demonstrated in four clinical trials, which used the antiretroviral medication tenofovir, either as a vaginal gel or as daily oral tenofovir disoproxil fumarate, alone or coformulated with emtricitabine. Importantly, however, two trials failed to demonstrate HIV protection with PrEP; low adherence to daily use of PrEP is the leading hypothesis to account for the lack of efficacy. Next steps in the field include rigorous evaluation of uptake and adherence to PrEP in implementation settings and research into next-generation PrEP agents with longer half-life and less user dependence.