Genes of the major histocompatibility complex (MHC) are one of the most significant genetic predictors of HIV and SIV disease outcome; however, in no case is MHC genotype alone sufficient to account for this durable HIV/SIV control. Killer immunoglobulin-like receptors (KIRs) interact with MHC molecules and have been implicated in control of HIV replication. They provide an attractive candidate to act in concert with protective MHC alleles in promoting viral control. While there is ample data demonstrating the association between KIR genotype and improved disease course, little is known about the mechanism through which KIRs promote HIV protection. As with MHC studies, macaques provide an important experimental model in which to address the role of KIRs in disease pathogenesis. This review focuses on the current understanding of the role of KIRs in HIV infection and outstanding questions for future study.