Abstract Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8+ memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell–based immunotherapy of cancer. Cancer Res; 75(24); 5187–93. ©2015 AACR.