Grant and colleagues have demonstrated that a combination of oral emtricitabine and tenofovir disoproxil fumarate taken as a chemoprophylaxis in men who have sex with men can provide a 44% reduction in the incidence of HIV. This international study, known as the Pre-Exposure Prophylaxis Initiative (iPrEx) trial, provides some of the first evidence for an oral strategy in considering HIV antiviral treatment as a preventive approach. The study does raise numerous questions in terms of long-term toxicity and complication, and how readily this approach might be initiated. That said, it does provide a tremendous opportunity to advance our efforts in HIV prevention strategies.