Clinical studies have demonstrated that immunization with the gp120 surface unit of the HIV-1 envelope protein does not lead to the induction of potent or broadly reactive neutralizing antibodies. In order to develop better immunogens, it is likely that we will need a more detailed understanding of the atomic level structure of epitopes on the native envelope glycoprotein. Data on the X-ray crystal structure of liganded and unliganded partial gp120 molecules have provided valuable information about the atomic level interaction of gp120 and neutralizing antibodies [9] [10] [11] [12] . The recent atomic level resolution of monoclonal antibody (MAb) b12 bound to the CD4 receptor binding site of the gp120 molecule provides new insights into how successful neutralizing antibodies access functionally conserved regions of the Env glycoprotein [13] . Crystal structures of complete monomeric gp120 and gp120-gp41 trimer complexes in their native unliganded form need to be elucidated, as these are the natural targets for neutralizing antibodies. This information is needed for multiple genetic subtypes of the virus and for transmitted strains of the virus. Coupled with this effort should be a program to make necessary improvements in electron tomography technology to gain a higher resolution of native Env spikes as they exist on virus particles [14] [15] [16] . An improved understanding of the structural basis of antibody binding to the HIV-1 Env glycoprotein will likely form the foundation for a rational program of novel vaccine design. Ongoing efforts to stabilize gp120 into more immunogenic forms or to scaffold conserved neutralization epitopes into foreign proteins may lead to more promising antibody responses.