The identification of MHC-class I-specific inhibitory receptors in humans and mice provided a first explanation of why NK cells can kill target cells that have lost or underexpress MHC-class I molecules but spare normal cells. However, the molecular basis of NK-mediated recognition and tumor cell killing revealed a higher degree of complexity. Thus, under pathological conditions, NK cells may express insufficient amounts of triggering receptors and target cells may or may not express ligands for such receptors. Here we briefly illustrate the main NK receptors and their cellular ligands and we delineate the major receptor/ligands interactions leading to NK cell activation and tumor cell lysis.