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Natural transmission of human immunodeficiency virus type 1 (HIV-1) occurs through gastrointestinal and vaginal mucosa. These mucosal tissues are major reservoirs for initial HIV replication and amplification, and the sites of rapid CD4(+) T cell depletion. In both HIV-infected humans and SIV-infected macaques, massive loss of CD4(+) CCR5(+) memory T cells occurs in the gut and vaginal mucosa within the first 10-14 days of infection. Induction of local HIV-specific immune responses by vaccines may facilitate effective control of HIV or SIV replication at these sites. Vaccines that induce mucosal responses, in particular CD8(+) cytotoxic T lymphocytes (CTL), have controlled viral replication at mucosal sites and curtailed systemic dissemination. Thus, there is strong justification for development of next generation vaccines that induce mucosal immune effectors against HIV-1 including CD8(+) CTL, CD4(+) T helper cells and secretory IgA. In addition, further understanding of local innate mechanisms that impact early viral replication will greatly inform future vaccine development. In this review, we examine the current knowledge concerning mucosal AIDS vaccine development. Moreover, we propose immunization strategies that may be able to elicit an effective immune response that can protect against AIDS as well as other mucosal infections.