Killer cell immunoglobulin‐like receptors (KIRs) have a central role in the control of natural killer (NK) cell function. The functions of the activating KIRs, as compared to those of the inhibitory KIR, have been more difficult to define due to difficulties in antibody‐mediated identification and their apparent low affinities for HLA class I. Immunogenetic studies have shown associations of activating KIRs with the outcome of autoimmune diseases, pregnancy‐associated disorders, infectious diseases and cancers. Activating KIR are thus thought to have important roles in the control of natural killer cell functions and their role in disease. In this review, we discuss current knowledge on activating KIR, their ligands and, their roles in the pathogenesis and potential therapy of human diseases.