Postexposure prophylaxis (PEP) with antiretroviral medication has been used as an HIV-prevention strategy for nearly 20 years. The fact that approximately 50 000 new HIV infections occur in the United States each year reflects marked underutilization of nonoccupational PEP (NPEP). There have been several advances in NPEP in the past 10 years. Clinical trials from different countries have demonstrated better tolerability, completion rates, and fewer drug–drug interactions with newer antiretroviral agents. Notably, there has been a shift from zidovudine-based to tenofovir-based regimens. Three-drug therapy is now favored for all potential HIV exposures. More recently, the US Public Health Service and the New York State Department of Health recommended tenofovir/emtricitabine and raltegravir as the first-line regimen universally for PEP. Advances in HIV testing technology may also allow shorter duration of follow-up HIV testing after a high-risk exposure. This review will discuss challenges with previously recommended regimens, newer potential candidate agents and the rationale for using them, intervals for laboratory monitoring, and cost considerations for NPEP. NPEP can be viewed as an educable moment and a potential bridge to preexposure prophylaxis, as part of a combination prevention package, for those who are likely to have recurrent higher-risk exposures. Thus, risk-reduction counseling should be an integral aspect of NPEP.