Natural killer (NK) cells provide innate defense against tumors and infections by virtue of potent capacities to immediately kill cellular targets and produce cytokines. These effector functions may potentially damage normal self-tissues unless they are kept in check by tolerance mechanisms that need clarification. Here, we discuss recent studies indicating that the NK cells acquire functional competence directly through engagement of their MHC-specific receptors by self-MHC. Ironically, these receptors were first identified in terms of recognizing target cell MHC class I molecules and inhibiting NK cells in effector responses. Other studies of NK cell tolerance are also discussed. Although these studies begin to clarify the means by which NK cell tolerance is achieved, much more investigation is needed because NK cell tolerance is relevant to clinical observations in patients with infections and cancer.