In the last 20 years, the study of human natural killer (NK) cells has moved from the first molecular characterizations of very few receptor molecules to the identification of a plethora of receptors displaying surprisingly divergent functions. Our laboratory has contributed to the description of inhibitory receptors and their signaling pathways, important in fine regulation in many cell types, but unknown until their discovery in the NK cells. Inhibitory function is central to regulating NK-mediated cytolysis, with different molecular structures evolving during speciation to assure its persistence. Only in the last ten years has it become possible to characterize the NK triggering receptors mediating natural cytotoxicity, leading to an appreciation of the existence of a cellular interaction network between effectors of both natural and adaptive immunity. This report reviews the contemporary history of molecular studies of receptors and ligands involved in NK cell function, characterizing the ligands of the triggering receptor and the mechanisms for finely regulating their expression in pathogen-infected or tumor cells.