25 years after the first HIV/AIDS cases emerged in 1981, the disease continues to spread worldwide, with about 15 000 new infections every day. Although highly active antiretroviral therapy (HAART) has greatly reduced the rate of HIV infection, and the spread of the epidemic, this effect has largely been seen in developed countries. More than 90% of HIV-infected people live in developing countries, most of whom do not have access to this treatment. The development of efficient, widely available, and low-cost microbicides (gels and creams can be applied topically before sex) to prevent sexually transmitted HIV infections should be given high priority. We review different categories of microbicide drugs and lead compounds, their mechanism of action, current status of development, and progress in phase III trials.