The skin and mucosa are the first line of defense of the organism against external agents, not only as a barrier between the body and the environment but also as the site of initiation of immune reactions. The immunocompetent epidermal cells which act as antigen-presenting cells (APC) are Langerhans cells (LC). Many indirect and/or direct experimental data have shown that LC may be a privileged target, reservoir and vector of dissemination for the human immunodeficiency virus (HIV) from the inoculation sites (mucosa?) to lymph nodes where the emigrated infected LC could infect T lymphocytes. In vitro infection confirms their permissivity to viral replication. HIV infection may modify the APC function of LC which could contribute to amplify the immunosuppressive state found in AIDS. Furthermore, mechanisms leading to the re-activation of viral expression at the cutaneous level need to be explored. An ideal animal model may readily clarify the role of LC in AIDS pathology and in transmucosal infection.