The innate immune system is the first line of defence in response to pathogen infection. Natural killer (NK) cells perform a vital role in this response with the ability to directly kill infected cells, produce cytokines, and cross-talk with the adaptive immune system. These effector functions are dependent on activation of NK cells which is determined by surface receptor interactions with ligands on target cells. Of these receptors, the polymorphic killer immunoglobulin-like receptors (KIRs), which interact with MHC class 1 (also highly polymorphic), are largely inhibitory, and exhibit substantial genetic diversity. The result is a significant variation of NK cell repertoire between individuals and also between populations, with a multitude of possible KIR:HLA combinations. As each KIR:ligand interaction may have differential effects on NK cell activation and inhibition, this diversity has important potential influences on the host response to infections. Genetic studies have demonstrated associations between specific KIR:ligand combinations and the outcome of viral (and other) infections, in particular hepatitis C and HIV infection. Detailed functional studies are not required to define the mechanisms underpinning these disease associations.