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Sexual transmission of HIV is the principal mode of spread of HIV throughout the world. Whether the use of combination antiretroviral therapy will affect the sexual transmission of HIV remains to be seen. For an effect to occur, the viral load reductions seen within the blood need to be mirrored at a mucosal level, within the rectal tissues, the female genital tract and the semen of HIV-1-infected men. In part, this will be determined by the local concentrations of drugs within the genital tract. In this overview, we summarise the current knowledge on antiretroviral drug penetration into the male and female genital tracts. We also review studies that have investigated the effect of antiretroviral therapy on genital-tract shedding. The clinical implications of these studies are discussed. We conclude that the risk of HIV transmission exists as a spectrum, with many factors, both behavioural and biological, at interplay. It is conceivable that the use of antiretroviral therapy could reduce the spread of HIV from certain individuals. However, this idea is based on biological plausibility and surrogate marker data, rather than prospective population studies. In the worst-case scenario, antiretroviral therapy may simply increase the transmission of drug-resistant virus.