Langerhans cells (LC) are the first dendritic cells (DC) to encounter pathogens entering the body via mucosa or skin. Equipped with pattern recognition receptors (PRR), LC are able to detect and respond to these pathogens. An important PRR, in human exclusively expressed by LC, is the C-type lectin Langerin. Langerin forms a protective barrier against HIV-1 infection by binding and degradation of this virus. In addition, antigens targeted to Langerin are presented to T cells to induce an adaptive immune response. Therefore Langerin functions as an innate anti-viral defense mechanism and an antigen receptor involved in adaptive immune responses. Here, we review the role of Langerin in antiviral protection, its structural similarity to other C-type lectins, and how its function and polymorphisms influence the function of Langerhans cells.