Women from developing countries, in which the prevalence of HIV infection is very high, are at risk of becoming infected without having the possibility of personally controlling this risk. Therefore, there is an urgent need to develop anti-HIV vaginal microbicide strategies. This review considers the modes of entry of HIV through the mucosa of the female genital tract, the different classes of vaginal microbicide compounds, the mode of delivery of these drugs, the aims and methods of in vitro and animal experiments at the preclinical stage, the results of the Phase III trials conducted in different countries, including the ongoing assays, and the future orientations for the next 5 years with a discussion relative to antiviral resistance, combination strategies and development of new-generation compounds.