Human natural killer (NK) lymphocytes were originally identified by their large granular morphology and their ability to "naturally" kill virus-infected and malignant cells without any priming. Lacking the surface markers of either B or T cells, they constitute the third major lymphocytic population, representing 5-15% of circulating lymphocytes. Their functions are tightly regulated by a delicate balance of signals transmitted by at least four different families of germ-line encoded, non-rearranged activating/inhibitory receptors. Once activated, NK cells produce immunoregulatory cytokines, interact with other immune cells, and finally destroy aberrant/pathogen-infected cells inducing their lysis or their apoptosis. The identification of phenotypically and functionally distinct NK cell subsets has provided advances in understanding the crucial role of these highly specialized and efficient lymphocytes. Traditionally considered as innate cells, NK lymphocytes appear to represent a bridge between the two broad arms of the human immune system. They are not only potent cytotoxic effectors, but also multicompetent cells that can shape and regulate both the innate and adaptive immune responses. A better knowledge of their biology may allow the development of new NK-based therapies addressed to the treatment of infections, malignancies and autoimmune diseases.