Data indicate that resistance to HIV-1 disease involves an array of contrasting HLA genotypic effects that are subtle, but significant, particularly when these genetic effects are considered as a whole. Numerous reports attributing a role for HLA genotype in AIDS outcomes have been reported, and a few of these have been affirmed in multiple studies. Functional studies of immune cell recognition have provided clues to the underlying mechanisms behind some of the strongest HLA associations, suggesting the means by which relative resistance or susceptibility to the virus may occur. SIV infection in non-human primates has served as an invaluable model for understanding AIDS pathogenesis (in rhesus monkeys) and viral resistance (in chimpanzee). The effect of rhesus MHC class I molecules on the evolution of SIV has been convincingly described [19], and a recent study in humans has suggested that selection pressure conferred by HLA molecules is responsible for specific genetic variation in HIV-1 [114]. HIV-1 may eventually have conspicuous evolutionary effects on HLA and other AIDS restriction genes, a prolonged process that could have occurred in chimpanzee [92]. To prevent such an outcome, it will be necessary to approach the disease from many perspectives, andapply comprehensively the knowledge gained to the successful control of the virus.