Natural or experimental infection of the African sooty mangabey (SM) with the simian immunodeficiency virus (SIV) results in chronic high levels of virus replication but is associated with none of the debilitating immunopathology, including the marked CD4 T-cell depletion, persistent cell activation and acquired immunodeficiency, that afflicts nonnatural hosts such as SIV-infected Asian rhesus macaques (RM) and HIV-infected humans. Although SIV-infected RM have served as important models of AIDS given their remarkably similar course of disease to HIV-infected humans, deciphering the immune mechanisms that enable SIV-infected SM to resist disease development despite high viremia has yet to be defined. Intense studies for the past two decades using these nonhuman primate models have been conducted with the hope that this will yield better insight into the pathogenesis of AIDS, translating into the development of therapeutic strategies for HIV-infected individuals such as but not limited to identifying correlates of protective immunity that can be harnessed for the preparation of effective vaccines. Although much has been reported about SIV-specific adaptive immune responses in both the natural and unnatural hosts of SIV, we submit that innate immunity may play a larger than previously appreciated role in SIV pathogenesis, in particular during the period of acute infection. The purpose of this review is to therefore highlight the recent advances that have been made in understanding innate immune responses in SIVinfected SM and to discuss the role(s) of the major innate immune cell lineages that potentially contribute to disease resistance in this non-human primate species.