Infection with the human immunodeficiency virus-1 (HIV-1) must be considered as a primarily mucosal disease. On a worldwide basis, the absolute majority of HIV infections occur through mucosal surfaces of the genital and intestinal tracts, and the earliest and most dramatic immunologic alterations are induced by the virus in mucosal tissues. However, individual compartments of mucosal components of the immune system display remarkable differences with respect to dominant antibody isotypes, virus phenotypes, densities and origins of cells involved in innate and specific immunity, presence or absence of inductive sites, and routes of immunizations that induce humoral and cellular responses. In this regard, the mucosal immune system of the female and male genital tracts exhibit several features which are distinct from other mucosal tissues, including dominance of the IgG isotype, local as well as pronounced systemic origin of antibodies, the absence of organized lymphoepithelial inductive sites and limited humoral responses stimulated by local antigen administration. Furthermore, it is evident that, irrespective of the route of infection, HIV-1 induces easily detectable IgG but not IgA specific antibody responses. These differences must be considered in the design of protective vaccines against infection with HIV and other agents of sexually transmitted diseases. © 2007 Elsevier Ireland Ltd. All rights reserved.