According to information from UNAIDS, more than 42 million individuals are living with HIV worldwide. Most infected individuals live in developing countries where the availability of antiretroviral agents is still limited. As this pandemic is increasing largely through mucosal transmission, new methods of prevention are urgently needed. If available, agents that block HIV prior to or early after contact with mucosal epithelia would decrease the incidence of HIV infection and, therefore, potentially save millions of lives over the next few decades. Topically applied microbicides acting against HIV-1 can be subdivided into four subgroups, including agents directly inhibiting pathogens, agents acting on genital pH, agents blocking pathogen entry and replication inhibitors. In addition, microbicides might also allow fighting against other sexually transmitted infections, such as herpes simplex viruses. With concerted efforts directed towards developing efficient microbicides, topical anti-infective compounds may well become a new weapon against sexually transmitted infections, including HIV, in everyday clinical practice.