The gastrointestinal and vaginal mucosa are the major routes of natural HIV transmission, with the former being the primary reservoir for virus replication. The crucial need for a global HIV vaccine underscores the effort to develop vaccines capable of eliciting mucosal immune responses. Vaccines that induce high levels of effective mucosal immunity should impact viral replication rate and prevent dissemination of virus from the mucosa into the systemic circulation. In our opinion, the major effort for effective HIV vaccine should be concentrated on generating protective immunity at the site of viral entry (i.e. the gastrointestinal and vaginal mucosae). Here we examine the current information regarding the role of mucosal immunity in prevention of HIV transmission and discuss strategies for mucosal AIDS vaccine development.