Approximately 60 vaginal microbicides are under development for the prevention of HIV/AIDS and other sexually transmitted pathogens. The history and current status of the field are discussed with emphasis on the lessons learned from recent clinical trials, along with an emphasis on the mechanisms involved in the sexual transmission of HIV and how this information influences microbicide development. Additionally, the current status of in vitro and animal systems used for evaluating microbicide efficacy, as well as the challenges involved in developing more appropriate and practical assays, are discussed. Also discussed are the challenges that face the microbicide product development field in meeting US Food and Drug Administration requirements regarding product safety and stability.