Natural killer (NK) cells are important elements of innate immunity, and a large body of evidence supports the significant role of NK in immune surveillance against infections and tumors. Regulation of cytotoxic activity is mediated through activating and inhibitory receptors expressed on the cell surface. NK cells are key players of allogeneic hematopoietic stem cell transplantation (allo-SCT), and previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. Biology of human NK cells is an area of active research. Exploitation of the molecular mechanisms regulating NK maturation, tolerance to self, and NK-mediated cytotoxicity will help in the development of innovative NK cell immunotherapy methods.