MHC-specific Natural Killer inhibitory receptors display a conserved and fundamental function in the regulation of NK-mediated cytolysis. Their importance is substantiated by the fact that during speciation different molecular receptor structures have evolved to maintain inhibitory regulation of NK cells. The information gained during these last twenty years begins to be fruitfully used in the therapy of leukemias, but a lot has to be still done. In particular, we need to understand the role of activating KIR and their ligand(s), since their role in the course of different viral diseases is still intriguing.