As the human immunodeficiency virus and sexually transmitted disease epidemics advance relentlessly, it is clear that an armamentarium of therapeutic and preventive methods will be essential to their containment. Topical microbicides--self-administered prophylactic agents applied to the vagina or rectum in various formulations--could be a crucial addition to that necessary armamentarium. This article provides an update on the dramatically broadening array of approaches being pursued in microbicide research and development and identifies critical challenges to progress.