The development and function of natural killer (NK) cells is dictated by signals received through activating and inhibitory receptors expressed on the cell surface. During their maturation in the bone marrow, NK cells undergo an education process that ensures they are tolerant to healthy peripheral tissues. Several recent studies advance our understanding of self-tolerance mechanisms at work in NK cells. These studies demonstrate that the developmental programming in NK cells is not fixed, and that perturbations to the peripheral environment (via transplantation or viral infection, for example) greatly influence the ability of mature NK cells to mount an effector response. This newfound ability of mature NK cells to be “re-educated” may be clinically applicable in the immunotherapeutic use of NK cells against infection and cancer.