Upon viral exposure, antibodies serve as a first line of defense and can act by preventing infection or reducing the viral burden. The ability of antibodies to confer protection against HIV has been demonstrated by several studies using the passive transfer of neutralizing antibodies in the non-human primate challenge model. Therefore, efforts have been made to induce a similarly protective humoral immune response by vaccination with antigens derived from HIV. Thus far, the results have been disappointing. Humoral immune responses elicited via vaccination display activities that are generally much less potent and broad as compared to those induced during natural infection. However, recently there have been increased efforts to systematically identify and compare the epitopes potentially critical to the generation of protective antibody responses in the hope that this will lead to improved strategies and superior immunogen design. As a critical part of this process, novel methods to monitor protective antibody responses will also need to be vigorously explored and improved, then validated in both preclinical and clinical settings.