After decades of mouse and human research, we now know that natural killer (NK) cells have unique properties including memory. Although initially described as major histocompatibility complex (MHC) unrestricted killers, NK cells have several families of receptors that directly recognize MHC including Ly49 receptors in the mouse and killer immunoglobulin-like receptors (KIR) in humans. The strength of this signal is determined by polymorphisms in NK cell inhibitory receptor genes and their MHC ligands inherited on different chromosomes. Inhibitory receptors protect “self”-expressing normal tissue from being killed by NK cells and protecting against autoimmunity. Therefore, for NK cells to kill and produce cytokines, they must encounter activating receptor ligands in the context of “missing self” that occurs with some viral infections and malignant transformation. The second property of inhibitory receptors is to educate or license NK cells to acquire function. This is best demonstrated in the mouse and in humans by enhanced function on self-inhibitory receptor-expressing NK cells when in a host expressing cognate ligate. In contrast, NK cells without inhibitory receptors or with nonself-inhibitory receptors are relatively hyporesponsive. The basic biology of NK cells in response to cytokines, education, and viruses will translate into strategies to manipulate NK cells for therapeutic purposes.