Natural Killer (NK) cells are innate immune cells with a primary role in the immune surveillance against non-self-cells. NK cell recognition of "self" relies on the surface expression on autologous cells of MHC class I (MHC-I) molecules. Either the absence or the down-modulation of MHC-I on target cells "license" NK cells to kill threatening tumor-transformed or virally infected cells. This phenomenon is controlled by a limited repertoire of activating and inhibitory NK receptors (aNKRs and iNKRs) that tunes NK cell activation and effector functions. Hence, the calibration of NK cell alloreactivity depends on the ability of iNKRs to bind MHC-I complex and these interactions are key in regulating both NK cell differentiation and effector functions. Indeed, the presence of iNKRs specific for self-MHC haplotypes (i) plays a role in the "licensing/education" process that controls the responsiveness of mature NK cells and prevents their activation against the "self" and (ii) is exploited by tumor cells to escape from NK cell cytotoxicity. Herein, we review our current knowledge on function and clinical application of NKG2A, a C-type lectin iNKR that binds specific haplotypes of human leukocyte antigens early during the NK cell maturation process, thus contributing to modulate the terminal maturation of NK cells as potent effectors against cancers cells. These NKG2A-mediated mechanisms are currently being exploited for developing promising immune-therapeutic strategies to improve the prognosis of solid and blood tumors and to ameliorate the clinical outcome of patients undergone allogeneic hematopoietic stem cell transplantation to treat high-risk hematologic malignancies.