Despite many years of intense scientific effort, the pathogenic mechanisms underlying the immunodeficiency that follows human immunodeficiency virus (HIV) infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a vaccine for AIDS. Important clues on the immunopathogenesis of primate lentiviral infections have been provided by comparative studies of two simian models of SIV infection: the non-pathogenic SIV infection of sooty mangabey, an African natural host species, and the pathogenic SIV-infection of non-natural host rhesus macaques, that develop a disease that closely resembles AIDS in humans. While the final mechanisms underlying the difference in infection outcome between these two species are still incompletely understood, a series of recent studies has allowed the identification of key similarities and differences between the two models of infection. In this article we summarize these findings and review the main implications in terms of HIV pathogenesis, therapy, and vaccines.