So far, all efforts to engineer immunogens that would elicit broadly reactive anti-HIV neutralizing antibody responses have not been successful. In the past few years, however, key information on the structure of the epitopes recognized by several broadly reactive anti-HIV neutralizing antibodies (NAbs), the structures of these NAbs themselves and the molecular interaction between these NAbs and their epitopes has emerged, that promises to guide the design of better immunogens. In order to enhance the immunogenicity of conserved neutralization epitopes on Env, certain modifications such as variable loop-deletion, elimination of glycosylation sites, or epitope-repositioning, are being investigated. So far, however, all available data from immunization studies indicate that the effect such structural modifications have on Env immunogenicity is unpredictable. This implies that despite the significant progress made in elucidating the interaction of NAbs with their targets at the molecular level, a significant iterative effort is required to identify immunogens that would elicit the much anticipated broad anti-HIV neutralizing antibody responses.