Over the last two decades, use of SIV for experimental infection of Asian macaques has provided important leads in the quest for an AIDS vaccine, served as the genesis of recombinant SIV/HIV viruses (SHIV), and perhaps most importantly, helped establish or confirm biological relevance for a variety of hypotheses related to the host immune response to infection and the corresponding viral strategies for evading that response. The env genes of HIV-1 and SIV encode proteins bearing a high degree of structural similarity and sharing an identical suite of essential functions. The Env complexes formed by these proteins are present on the surface of virus-producing cells and virions, where they are the primary targets of the host neutralizing antibody response. In this review, we briefly describe the similarities between HIV-1 infection and SIV experimental models, then focus specifically on the use of the SIV/macaque model as a tool for understanding the humoral immune response to infection and resistance to antibody-mediated neutralization in HIV infection and AIDS.