Autoimmune diseases are chronic conditions resulting from a loss of immunological tolerance to self-antigens. Recent observations have supported an ever-broader role for innate immune responses in directing and regulating adaptive immunity, including responses to self. This review summarizes recent findings supporting important functions of natural killer (NK) cells in regulating autoimmunity. A close survey of the current literature reveals multiple steps where NK cells can regulate inflammation and intervene in loss of self-tolerance. Importantly, the findings also caution against inferring a similar role for NK cells in all autoimmune phenomena or during separate stages of the same disease. Indeed, NK cells may have different influences during the priming and the effector phases of disease. Hence, an increased understanding of the involvement of NK cells in inflammation and infection should provide new insights into the pathogenesis of autoimmune disease.