Langerhans cells (LCs) are the resident dendritic cells (DCs) of epidermis in human mucosal stratified squamous epithelium and the skin. A phenotypically similar DC has recently been discovered as a minor population in the murine dermis. In epidermis, LCs function as sentinel antigen-presenting cells that can capture invading viruses such as herpes simplex virus (HSV), varicella-zoster virus (VZV) and human immunodeficiency virus (HIV). This interaction between LCs and viruses results in highly variable responses, depending on the virus as discussed in this review. For example, HSV induces apoptosis in LCs but HIV does not. LCs seem to be the first in a complex chain of antigen presentation to T cells in lymph nodes for HSV and possibly VZV, or they transport virus to T cells, as described for HIV and maybe VZV. Together with epidermal keratinocytes they may also have a role in the initial innate immune response at the site of infection in the epidermis, although this is not fully known. The full spectrum of biological responses of LCs even to these viruses has yet to be understood and will require complementary studies in human LCs in vitro and in murine models in vivo.