Publisher Summary Integrated with other immune cells, natural killer (NK) cells contribute to host anti-microbial and anti- tumor immunity. The provision of early defence mechanisms against viral infections, particularly herpes viruses, is perhaps the most important clinical effect by NK cells, but it was their cytotoxic potency against tumor cells that brought about their discovery. Their ability to lyse tumor cells in vitro without the requirement of prior immune sensitization of the host also gave them their name. NK cells are now well characterized with respect to their origin, differentiation, receptor repertoire, and effector functions properties. NK cells mediate killing of many different types of murine and human tumor cell lines in vitro. Several experimental studies in mice have also shown a role for NK cells in rejection responses against grafted murine tumor cell lines and against experimentally induced and spontaneously developing tumor in mice. Like cytotoxic T cells, NK cells possess different effector functions by which they mount anti- tumor responses. Two major mechanisms are used to induce target cell apoptosis, granule exocytosis and death receptor stimulation. NK cells can also produce many different cytokines as well as chemokines, some of which have a direct effect on tumor. The best studied cytokine in this respect is IFN-γ, a cytokine which decreases proliferation, enhances autophagy, limits metabolic activity of tumor cells and inhibits angiogenesis. IFN-γ produced by NK cells might also play a role in the regulation of killing by death receptors, either by downregulating anti-apoptotic proteins, or by upregulating caspases that are essential for death receptor-mediated apoptosis.