Human immunodeficiency virus-1 (HIV-1) infection occurs primarily via genital mucosal tissues and the cellular mechanisms that affect HIV-1 acquisition are largely unclear. Langerhans cells (LCs) are professional antigen presenting cells lining the mucosal stratified squamous epithelium. It is becoming evident that LCs have different functions in HIV-1 transmission. HIV-1 can infect mucosal LCs, which subsequently efficiently transmit the virus to T cells in the lymphoid tissues. However, this seems to be dependent on the activation status of LCs, as immature LCs prevent HIV-1 infection by clearing invading HIV-1 though the C-type lectin langerin. Recent data demonstrate that co-infections with sexual transmitted infection (STIs) negate the protective function of LCs by different mechanisms, thereby allowing LC infection with HIV-1 and subsequently HIV-1 transmission. Here, we will discuss the function of LCs under normal circumstances and in the presence of STIs or inflammation. A better understanding of LCs function during homeostasis and inflammation is necessary for the development of new strategies to prevent HIV-1 infection.