Chemoprophylaxis may be a prevention strategy for the sexual transmission of human immunodeficiency virus (HIV). Evidence suggests that condom use has waned with the availability of antiretroviral medication, at least in some resource-rich settings. Barrier methods of HIV prevention have inherent problems, and the potential for failure. Microbicide research has focused primarily on male-to-female transmission. Analogous to post-exposure prophylaxis, HIV prevention may be achieved by pre-exposure prophylaxis in some settings. Research in this potential strategy may be rewarding.