Human Natural Killer cells express a large array of surface receptors that are involved in the regulation of the different NK cell functions. Some of these receptors, by sensing the expression of HLA class I on potential target cells, deliver negative signals that inhibit the NK-mediated killing. In the absence of such inhibitory interactions, other receptors are allowed to transduce activating signals that result in NK-mediated attack of tumor- or virus-transformed cells. The function of these main activating receptors is supported and enhanced by the simultaneous engagement of different co-receptors. Finally, the ability of NK cells to interact with normal, non-transformed other cells such as dendritic cells (DC) appears to crucially contribute to the regulation of both innate and adaptive immune responses.