Natural killer (NK) cells are part of the innate-immune system and respond rapidly to a variety of insults via cytokine secretion and cytolytic activity. Their main function is first line of innate immunity across viral, bacterial and parasitic infections. NK-cells are not solely killers but can also act as regulators of adaptive immunity. It is evident from literature that NK-cells are deeply involved in autoimmunity, but the question is how and why they act as a two edged weapon. Number of circulating NK-cells can be frequently altered depending on the disease taken into consideration. Cytokine milieu, the microenvironment in which they mature and other stimuli acting on different cell surface receptors may differently trigger NK-cells response and influence their role in autoimmune diseases. Functional differences between NK-cells at different anatomical sites, the adaptability of NK-cells effector responses and genetic factors may also explain differences in such responses. Thus, NK-cell alterations may be associated with increased autoimmunity and the modulation in the number of circulating NK-cells seems to be a primary event rather than an active inflammation/drug administration consequence during inflammatory/autoimmune processes, playing a fundamental role in the pathogenesis of a number of autoimmune diseases.