Microbicide clinical trials have dominated biomedical HIV prevention research in the past decade. Two generations of microbicides have gone through large-scale human clinical trials. Candidate microbicides assessed in clinical trials in Africa have fallen into the categories of surfactants, polyanionic entry inhibitors, or vaginal milieu protectors. These include compounds such as nonoxynol-9, SAVVY, cellulose sulphate, Carraguard, PRO 2000, and BufferGel. Disappointingly, none of the products have shown efficacy against HIV. Each successive trial has benefited from the lessons learned in preceding trials. The trials have provided important lessons in basic, clinical, social, and behavioural science. More importantly, we have learned that the concept of a vaginally inserted product for HIV prevention is acceptable by women. We have now reached an end of an era of clinical testing with non-HIV-specific microbicides and move forward to testing novel strategies of antiretroviral therapeutic products such as preexposure prophylaxis (PrEP) for HIV prevention. PrEP for vaginal administration in various formulations is being tested to continue our commitment to providing more HIV prevention options to millions of women worldwide.