Sexual transmission of HIV is the most common mode of infection in the global HIV epidemic. In the absence of an effective vaccine, there is an urgent need for additional strategies to prevent new HIV infections. An emerging body of evidence now indicates that Langerhans cells (LC) are initial cellular targets in the sexual transmission of HIV, and CD4- and CCR5-mediated infection of LC plays a crucial role in virus dissemination. However, interactions between HIV and LC are complex. For example, it is evident that HIV can interact concomitantly with non-LC dendritic cells in two separate and distinct ways: a CD4- and CCR5-dependent infection pathway and a CD4- and CCR5-independent capture pathway mediated by DC-SIGN, a C-type lectin molecule. Thus, there may be multiple ways by which HIV interacts with target cells in the genital mucosa. This review focuses on the recent advances regarding the cellular events that may occur during heterosexual transmission of HIV.