Natural transmission of HIV occurs through mucosal surfaces. New information in immunology, virology and vaccinology has emerged regarding strategies for development of new mucosal vaccines against HIV. The intestinal mucosa represents a major site of HIV replication and amplification, and the initial site of CD4+ T-cell depletion. Local mucosal CD8+ cytotoxic T-lymphocytes (CTLs) and mucosal antibody can control AIDS virus replication within local tissues prior to systemic dissemination and can be more effective than a systemic immune response. Mucosal HIV vaccine delivery should be considered among the most effective immunization routes in the induction of mucosal antibody and CD8+ CTLs and protection against mucosal infection. New mucosal vaccine strategies, such as prime-boost, using a new generation of mucosal adjuvants, a synergistic combination of cytokines, chemokines, costimulatory molecules, CpG oligodeoxynucleotides, and targeting lymph nodes which drain mucosal sites, show promise to improve the efficacy of mucosal vaccines.