Many species of African nonhuman primates are naturally infected with simian immunodeficiency viruses (SIVs) in the wild and in captivity. In contrast to HIV-infected humans, these natural SIV hosts typically do not develop AIDS, despite chronic infection with a highly replicating virus. In this Review, we discuss the most recent advances on the mechanisms of protection from disease progression in natural SIV hosts, with emphasis on how they differ from pathogenic HIV/SIV infections of humans and rhesus macaques. These mechanisms include: (i) resolution of immune activation after acute infection, (ii) restricted pattern of target cell infection, and (iii) protection from mother-to-infant transmission. We highlight the areas that should be pursued in future studies, focusing on potential applications for the treatment and prevention of HIV infection.