Human Natural Killer cells (NK) were originally identified on the capability of killing certain tumor cell lines in the absence of deliberate previous stimulation. Recently, a novel concept has emerged indicating that the actual role of NK cells is not only confined to the destruction of virus-infected cells or tumors. This is particularly relevant during the early phases of acute inflammation, secondary to infection. Various studies were focused on the crosstalk between NK cells and monocyte-derived dendritic cells and more recently on the involvement of plasmocytoid dendritic cells, mast cells, basophils, eosinophils, and neutrophils. This is in accord with the fact that NK cells from blood can be attracted to peripheral tissues by several chemokines released during inflammatory responses. In contrast, a minority of NK cells from blood expresses receptors for homing to lymphoid tissues. In particular, the function of NK cells is regulated by a balance between opposite signals delivered by a set of HLA class I specific inhibitory receptors and by a number of activating receptors and co-receptors responsible for NK cell triggering. By the combined use of these receptors, NK cells can discriminate between normal HLA class I+ cells and cells that have lost the expression of HLA class I molecules as a consequence of tumor transformation or viral infection. For over a decade, our research group has been studying NK cells identifying novel functional molecules expressed on different subsets of NK cells and investigating NK cells derived from patients affected by primary immune deficiencies. Recently, in our laboratory, we also analyze the expression pattern and the function of inhibitory and activating NK receptors on different NK subsets derived from patients with epithelial ovarian carcinoma subjected to primary surgery. To better understand NK-mediated lysis mechanisms, a special attention was paid on the interaction between inhibitory/activating NK receptors and HLA class I molecules/tumoral ligands. Indeed, this may reflect a differential involvement of these receptors in controlling the process of tumor growth. These immunological analyses are possible thanks to the isolation in our laboratory of monoclonal antibodies that can be applied in these specific experiments where most commercially available reagents can not be used. At last, by generating monoclonal antibodies, our research group have identified novel NK cell receptors and markers that allowed a further characterization of different human NK cell subsets.