BACKGROUND: Microbicides are topical compounds that could prevent sexually transmitted infections. Several compounds have demonstrated activity both in vitro and in animal models, but none has been approved for use in humans. METHODS: A review of >100 recent publications from MEDLINE (through October 2005) and abstracts presented at recent conferences was undertaken to describe the current status of microbicide research and to delineate why microbicides are not yet available. RESULTS: More than 15 candidate microbicides are currently being studied in clinical trials. Their mechanisms of action include disruption of the viral membrane by surfactants, maintenance of an acidic vaginal pH, binding to the viral envelope to block receptor binding, and blocking of receptors; they may also be combined with antiretroviral drugs. The development of safe and effective microbicides has been delayed by limitations in understanding the biological processes of human immunodeficiency virus (HIV) transmission, difficulties in extrapolation from animal models, lack of established correlates of protection, and the need to enroll and follow large cohorts of high-risk participants for several years in order to demonstrate efficacy. CONCLUSIONS: Safe and effective topical microbicides are biologically plausible. Several trials that are under way may demonstrate the ability of microbicides to protect against transmission of HIV, but multiple challenges remain.