HIV preexposure prophylaxis (PrEP) has demonstrated efficacy in 4 studies: 1) the CAPRISA 004 trial of pericoital administration of 1% tenofovir gel showed moderate (39%) efficacy in reducing risk of HIV acquisition in young women; 2) the iPrEx trial of daily oral emtricitabine/tenofovir had moderate (44%) efficacy in reducing risk of HIV acquisition among high-risk men who have sex with men (MSM); 3) the Partners PrEP Study in African HIV-serodiscordant couples, in which the HIV-seronegative partner received daily oral tenofovir or emtricitabine/tenofovir, showed high efficacy (62% and 73%, respectively); and 4) the TDF2 trial in young heterosexual men and women in Botswana demonstrated 62% efficacy of daily oral emtricitabine/tenofovir. Greater adherence to PrEP is associated with greater efficacy. Resistance to tenofovir and emtricitabine have been rare and were primarily observed during PrEP initiation in those with acute HIV infection. PrEP has been found to be safe and well tolerated. The FEM-PrEP trial of oral emtricitabine/tenofovir and the VOICE trials of daily 1% tenofovir gel and oral tenofovir (both studies conducted in African women) did not show protective benefit, for reasons that currently remain unknown. The Bangkok Tenofovir Study of oral tenofovir in injection drug users, and the emtricitabine/tenofovir study arm of the VOICE trial, are ongoing. Establishing PrEP programs will be a great challenge and a great opportunity. This article summarizes a presentation by Connie L. Celum, MD, MPH, at the IAS-USA live continuing education course held in Chicago in June 2011, and includes updates on PrEP trial results reported since July 2011.