Heterosexual 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. Evidence from a variety of investigations, including epidemiologic studies on sexual transmission, in vivo studies in rhesus monkey, and ex vivo studies using human explant models, indicate that CD4/CCR5-mediated de novo infection of Langerhans cells (LCs) is a major pathway involved in sexual transmission of HIV (LCs primary gate keeper model). However, it has been recently revealed that Langerin (a C-type lectin receptor) expressed on LC inactivate HIV. Thus, there may be multiple ways by which HIV interacts with LCs in the genital mucosa. In light of the current HIV infection rates in heterosexuals and the absence of a prophylactic vaccine, prevention strategies, such as topical microbicides that block sexual transmission of HIV, are urgently needed. This review focuses on the recent advances regarding the role of LCs in heterosexual transmission of HIV, and the relationship between the LCs primary gate keeper model and current prevention strategies worldwide.