While cancer has been traditionally treated by chemotherapy, radiation, targeted therapies and surgery, a fifth pillar of cancer treatment, immunotherapy, has emerged over the past 10 years and revolutionized our war on cancer. The benchmark for drugs in this category has been set by the development of CD8 T cell checkpoint (CTLA-4 and PD-1/PD-L1) inhibitors. These therapies effectively expand and reactivate the pool of tumor-specific T cells leading to objective response rates of up to 50% in patients with certain cancers. However, the significant number of patients and cancer types that altogether fail or acquire resistance to these therapies highlights the need for novel immunotherapies that target alternate pathways and effector cells. Thus, there is renewed interest in harnessing the tumor-killing abilities of Natural Killer (NK) cells, though it has proven difficult to efficiently and specifically target these cells cancer patients. The commercial success of T cell checkpoint inhibitors has seen a swam of new biotech companies emerge with innovative or revised strategies that aim to harness the innate non-antigen dependent tumor lysis potential of NK cells. This review will focus on IL-15 biology in NK cells and proposes the development novel therapies aimed at this pathway in humans.