The worldwide infection rate for HIV-1 is estimated to be 14,000 per day, but only now, more than 20 years into the epidemic, are the immediate events between exposure to infectious virus and the establishment of infection becoming clear. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells, could reveal ways to block the sexual spread of the virus. In this review, we will discuss how our increasing knowledge of the ways in which HIV-1 is transmitted is shaping the development of new, more sophisticated intervention strategies based on the application of vaginal or rectal microbicides.