Natural killer (NK) cells destroy hazardous cells such as tumors and virus-infected cells immediately without the need for prior antigen stimulation. The activation of NK cells largely depends on the recently identified natural cytotoxic receptors (NCRs), which include three members: NKp46, NKp44 and NKp30. The NCRs are unique in their expression pattern that is almost conclusively confined to NK cells, and in their broad specificity towards a wide range of targets. However, very little is known about the ligands identity of the NCRs and so far the only ligands known are two virally derived molecules: the hemagglutinin protein of influenza viruses that directly binds and activates two of the NCRs; NKp46 and NKp44, and the human cytomegalovirus tegument protein, pp65, which binds the NKp30 receptor and inhibits its activation thus promoting survival of the virus. In this review we describe the function of the NCRs in various pathological conditions with a special emphasis on tumor targeting.