The mucosal immune system appears to be a major target of the HIV infection. Therefore, a strong pre-existing anti-HIV immune response in mucosal compartments might be able to prevent HIV infection. Conflicting views regarding the mechanisms of protection at mucosal sites, inferred by the contradictory results of mucosal vaccines in human clinical trials, attests to our lack of knowledge in understanding the human mucosal immune system. In this article, we briefly review the function of innate and adaptive immune responses and discuss current strategies and potential adjuvants in designing and delivering HIV vaccines through mucosal routes. © 2010 Elsevier Ltd. All rights reserved.