The discovery of an unexpected level of diversity among the killer cell immunoglobulin-like receptors has led to a search for their role in human disease. Due to their polymorphism and also that of their human leukocyte antigen class I ligands, these studies are difficult to perform and complex to interpret. Nevertheless, as the number of data sets increase, consistent trends and themes are beginning to emerge in both viral and inflammatory disorders. In this review, we summarize the findings from a number of disease association studies and discuss these in the context of the activating and inhibitory roles of the members of this gene family.