Leukocyte behavior is controlled by a balance of inhibitory and stimulatory signals generated on ligand binding to a complex set of receptors located on the cell surface. The killer cell immunoglobulin-like receptor (KIR) genes encode one such family of receptors expressed by natural killer (NK) cells, key components of the innate immune system that participate in early responses against infected or transformed cells through production of cytokines and direct cytotoxicity. KIRs are also expressed on a subset of T cells, where they contribute to the intensity of acquired immune responses. Recognition of self HLA class I ligands by inhibitory KIR allows NK cells to identify normal cells, preventing an NK cell-mediated response against healthy autologous cells. Activation of NK cells through stimulatory receptors is directed toward cells with altered expression of class I, a situation characteristic of some virally infected cells and tumor cells. The “missing self” model for NK cell activation was proposed to explain killing of cells that express little or no class I, while cells expressing normal levels of class I are spared. Studies performed over the last several years have revealed extensive diversity at the KIR gene locus,which stems from both its polygenic (variable numbers of genes depending on KIR haplotype) and multiallelic polymorphism. Given the role of KIR in both arms of the immune response, their specificity for HLA class I allotypes, and their extensive genomic diversity, it is reasonable to imagine that KIR gene variation affects resistance and susceptibility to the pathogenesis of numerous diseases. Consequently, the evolution of KIR locus diversity within and across populations may be a function of disease morbidity and mortality. Here we review a growing body of evidence purporting the influence of KIR polymorphism in human disease.