IL-15, a pleiotropic cytokine, stimulates generation of NK, NK-T, γδ, ILC1, and memory CD8 T cells. IL-15 disorders play pathogenetic roles in organ-specific autoimmune diseases including celiac disease. Diverse approaches are developed to block IL-15 action. IL-15 administered to patients with malignancy yielded dramatic increases in NK numbers and modest increases in CD8 T cells. Due to immunological checkpoints, to achieve major cancer therapeutic efficacy, IL-15 will be used in combination therapy, and combination trials with checkpoint inhibitors, with anti-CD40 to yield tumor-specific CD8 T cells, and with anticancer monoclonal antibodies to increase ADCC and antitumor efficacy, have been initiated.