Family physicians often encounter situations in which postexposure prophylaxis (PEP) with antiretroviral medications against human immunodeficiency virus (HIV) may be indicated. When the exposure source's HIV status is unknown and testing of the source is possible, use of a rapid HIV test kit may facilitate decision making at the point of care. When PEP is given, timing and duration are important, with data showing PEP to be most effective when initiated within 72 hours of exposure and continued for four weeks. Although two-drug PEP regimens are an option for some lower risk occupational exposures, three-drug regimens are advised for nonoccupational exposures. Sexual assault survivors should be given three-drug PEP regardless of assailant characteristics. In complicated situations, such as exposure of a pregnant woman or when a source is known to be infected with HIV, expert consultation is advised. In most cases, PEP is not indicated after an accidental needlestick in the community setting. Health care volunteers working abroad, particularly in areas of high HIV prevalence or where preferred PEP regimens may not be readily available, often choose to travel with personal supplies of PEP. Patients presenting for care after HIV exposure should have baseline testing for HIV antibodies, and follow-up HIV antibody testing at four to six weeks, three months, and six months after exposure.