This review addresses the physiological role of class I-mediated inhibition of NK cell lysis. It is suggested that several distinct activating receptors can stimulate NK lysis, all of which can be inhibited by class I molecules on the target cell. Evidence that most or all peptides that bind a class I molecule can cause inhibition is discussed, supporting a model in which NK cells detect loss of class I molecules, rather than loss of specific peptide/class I complexes. Finally, the acquisition of self-tolerance among NK cells is addressed with respect to data suggesting that autoaggressive NK cells are not deleted but rather exhibit altered characteristics which may render them unable to lyse autologous cells.