Dendritic cells (DCs) are thought to mediate HIV-1 transmission but it is becoming evident that different DC subsets at the sites of infection have distinct roles. In the genital tissues, two different DC subsets are present: the Langerhans cells (LCs) and the DC-SIGN(+)-DCs. Although DC-SIGN(+)-DCs mediate HIV-1 transmission, recent data demonstrate that LCs prevent HIV-1 transmission by clearing invading HIV-1 particles. However, this protective function of LCs is dependent on the function of the C-type lectin Langerin: blocking Langerin function by high virus concentrations enables HIV-1 transmission by LCs. Here, we will discuss the molecular mechanisms involved in HIV-1 transmission and viral clearance. A better understanding of these processes is crucial to understand and develop strategies to combat transmission.