Natural killer (NK) cells are lymphocytes of the innate immune system that exert a potent function against infected and tumor cells. Although NK cells were originally defined by their capacity to lyse target cells and produce interferon (IFN)-gamma without prior activation, more recent studies found that NK cells display also a potent regulatory function. Following engagement of surface receptors by other cells or signalling by soluble molecules, NK cells release cytokines able to influence the outcome of an immune response. Since their discovery in the 1970s, the biology of NK cells has been deeply investigated; nevertheless some aspects of their maturation process, activation mechanisms, and tissue distribution remain still obscure. These review will focus on three major issues regarding NK cell regulation. In particular we aim to discuss: (i) how NK cells become tolerant to self-tissues during their maturation; (ii) how NK cells become activated, with a particular attention to dendritic cell (DC)-mediated mechanisms of NK cell priming; (iii) where NK cells play their functions and how NK cell tissue distribution can favour their capacity to skew T cell responses.