This article reviews the status of current research evaluating oral preexposure prophylaxis (PrEP) for prevention of HIV infection in high-risk populations. In animal model studies, the use of antiretrovirals has been shown to be effective in preventing HIV acquisition. Early-phase PrEP studies have established safety in humans. Currently, more than 20,000 men and women will soon be enrolled in studies of oral or topical chemoprophylaxis, testing a variety of drug delivery methods including tenofovir disoproxil fumarate (TDF) gel applied vaginally or rectally, as well as oral PrEP using TDF by itself or coformulated with emtricitabine (FTC). The largest global PrEP trial in men who have sex with men (MSM), known as iPrEx has demonstrated that oral chemoprophylaxis can decrease HIV incidence in this population. Although TDF/FTC PrEP was generally well tolerated, side effects such as nausea, as well as mild and reversible renal abnormalities were increased among the men who received active medication, suggesting that PrEP users will need ongoing PrEP clinical monitoring. The prophylactic benefits of TDF/FTC were substantially attenuated by nonadherence, indicating that effective PrEP implementation programs will need to focus on this behavioral variable, in addition to safer sex counseling. This article considers biological, policy, and practical implications of large-scale oral PrEP implementation.