Natural killer (NK) cells represent the first identified members of the wide family of Innate Lymphoid Cells (ILCs). Over time, NK cells shifted from being considered “null” and “non-specific” cells to represent important immune effectors respectful of self, highly cytotoxic against virus-infected and cancer cells, capable of releasing immunostimulatory cytokines and regulating the innate and adaptive immune responses. We know now that NK cells are very heterogeneous both in terms of phenotype and function, and their functional spectrum is regulated by integrated signals delivered by a huge amount of activating and inhibitory receptors and coreceptors. The quality and intensity of the NK cell activity depend on the relative ratio of these receptors and their soluble or membrane-bound ligands. Unfortunately, in the tumor context, the inhibitory signals often overcome the activating ones because of several molecular mechanisms mediated by cell-to-cell contacts and the release of soluble molecules including cytokines. The present chapter overviews these mechanisms spanning from the prototypic KIR/HLA class I interactions to the most recently discovered immune checkpoints as the B7-H3 receptor/B7-H3 axis. We also describe the activity of molecules acting as intracellular checkpoints such as CIS, and the CXCR4-CXCL12 interaction impacting the NK cell-mediated control of tumor dormancy.