HLA-DR-expressing cells comprise an intriguing group of NK cells, which combine phenotypic characteristics of both NK cells and dendritic cells. These cells can be found in humans and mice; they are present in blood and tissues in healthy conditions and can expand in a spectrum of pathologies. HLA-DR NK cells are functionally active: they produce proinflammatory cytokines, degranulate, and easily proliferate in response to stimuli. Additionally, HLA-DR CD11c NK cells seem able to take in and then present certain antigens to CD4 and CD8 CD11c T cells, inducing their activation and proliferation, which puts them closer to professional antigen-presenting cells. It appears that these NK cells should be considerable players of the innate immune system, both due to their functional activity and regulation of the innate and adaptive immune responses. In this review, for the first time, we provide a detailed description and analysis of the available data characterizing phenotypic, developmental, and functional features of the HLA-DR NK cells in a healthy condition and a disease.