Data supporting the efficacy of HIV postexposure prophylaxis (PEP) come largely from a small number of older studies and case reports in health care workers, studies of transmission from infected mothers to their infants, and animal studies. These data also provide support for the current recommendations regarding duration of PEP and the window of time within which PEP should be started. Although much of the available data are from experience with older 2-drug regimens, newer potent 2- and 3-drug regimens are increasingly used in occupational exposure management, and drugs with mechanisms of action targeting early events in infection (eg, entry inhibitors, integrase inhibitors) may in the future become attractive options. Nonoccupational PEP remains controversial, although its feasibility and safety have been demonstrated in a number of programs. Existing recommendations generally call for its use within 72 hours of high-risk contact with a high-risk or HIV-infected source individual. This article summarizes a presentation on PEP for HIV infection made by Raphael J. Landovitz, MD, at the IAS-USA continuing medical education course held in Los Angeles in February 2009. The original presentation is available as a Webcast at www.iasusa.org.