As HIV prevalence climbs globally, including more than 50 000 new infections per year in the United States, we need more effective HIV prevention strategies. The use of antiretrovirals for preexposure prophylaxis (PrEP) among high-risk persons without HIV is emerging as one such strategy. Randomized, controlled trials have demonstrated that once-daily oral PrEP decreased HIV incidence among at-risk men who have sex with men and African heterosexuals, including serodiscordant couples. An additional randomized, controlled trial of a topical pericoital antiretroviral microbicide gel decreased HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population. The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee reviewed these studies and additional data in May 2012 and voted to advise the approval of oral tenofovir-emtricitabine for PrEP in high-risk populations. On 16 July 2012, the FDA recommended that this combination medication be approved for use as PrEP in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic.