The natural killer gene complex encodes proteins, some of which are structurally unrelated, that impact on NK-cell function. Detailed analyses have indicated that these molecules are involved in NK-cell recognition, activation, and inhibition. The importance of this genomic region is highlighted by studies indicating that NKC-associated genes significantly influence NK cell-mediated innate host defense against life-threatening pathogens and that the NKC is conserved among diverse species. Thus, further elucidation of the NKC and its gene products will provide a genetic basis for understanding innate immunity and NK-cell activity at the molecular level.