HIV microbicides are topical, self-administered products aimed at preventing or reducing HIV infection in women and may represent the most promising strategy for combating the HIV/AIDS epidemic at the present time. Although a safe and effective microbicide has yet to be identified, all products tested in Phase III trials to date have been vaginal gels containing non-specific compounds with modest potency that had to be applied close to the time of sexual intercourse. Issues regarding these early generation products were further complicated by widely publicized cases of halted efficacy trials. However, as a result of each of these challenges, new information and essential lessons have emerged for the field. These lessons have resulted in a meaningful increase in microbicide development efforts focusing on compounds with highly potent and HIV-specific mechanisms of action, combination products, novel formulations, and carefully designed pharmacokinetic and pharmacodynamic evaluations, all of which are reasons for renewed confidence that a safe and effective microbicide is achievable.