Microbicides are products that can be applied to vaginal or rectal mucosa with the intent of preventing, or at least significantly reducing, the transmission of sexually transmitted infections including HIV-1. Unfortunately, the last 5–10 years of microbicide research have generated a number of disappointments. Large scale phase 2B/3 studies or topical microbicides have failed to demonstrate product efficacy, have been stopped prematurely for futility, or in the worst case scenario have possibly demonstrated microbicide induced harm including increased risk of HIV acquisition. Although the CAPRISA 004 study of vaginal peri-coital tenofovir gel demonstrated a significant reduction in HIV acquisition (39%; p = 0.017), the most recently completed microbicide effectiveness study, MTN-003 (the VOICE study), did not demonstrate the effectiveness of daily tenofovir gel, largely due to product non-adherence by study participants. However, the ongoing FACTS-001 study has the potential to confirm the results of the CAPRISA 004 study and may lead to licensure of tenofovir gel. In addition, current microbicide research is increasingly focused on technology, such as intravaginal rings, that provide sustained release of antiretrovirals to the cervicovaginal mucosa and may minimise adherence problems associated with peri-coital or daily use of vaginal gels. Two Phase 3 studies of a dapivirine vaginal ring are currently ongoing. The development of combination products that might provide contraceptive and antiretroviral drug delivery is also gathering momentum. Rectal microbicide research has moved from Phase 1 to Phase development. The MTN-017 study, which will be conducted in the USA, Peru, Thailand, and South Africa, will evaluate the safety and acceptability of oral Truvada and rectal tenofovir gel in men who have sex with men and transgender women. This talk will provide a comprehensive update on the challenges and opportunities associated with microbicide development.