Development of a safe and effective vaccine for HIV-1 infection is a critical global priority. However, the nature of host-virus interactions that lead to early immunosuppression and CD4 depletion, HIV-1 diversity, and the inability of the immune system to eliminate the latently infected CD4 pool of cells has to date thwarted successful vaccine development. Moreover, both the initial antibody-inducing vaccine (protein envelope gp120) and cell-mediated vaccine (recombinant adenovirus containing HIV-1 genes) strategies have failed in efficacy trials, and the latter cell-mediated vaccine appeared to have caused enhanced HIV-1 acquisition. Thus basic and translational research to understand why current vaccines have failed and elucidation of new mechanisms of virus control at mucosal surfaces is essential for eventual successful development of a preventive HIV-1 vaccine.