The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmacodynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2-3 years.