Natural killer (NK) cells recognize deranged cells that display stress receptors or loss of major histocompatibility complex (MHC) class I. During development, NK cells become "licensed" only after they encounter cognate human leukocyte antigen (HLA) class I, leading to the acquisition of effector function. NK cells can be exploited for cancer therapy in several ways. These include targeting with monoclonal antibodies alone or combined with ex vivo and in vivo NK cell activation to facilitate adoptive immunotherapy using donor-derived NK cell products to induce graft-vs-tumor effects. In the adoptive transfer setting, persistence and in vivo expansion requires lymphodepleting chemotherapy to prevent rejection and provide homeostatic cytokines (such as IL-15) that activate NK cells. IL-15 has the advantage of avoiding regulatory T-cell expansion. Clinical applications are currently being tested. To enhance in vivo expansion, IL-2 has been used at low doses. However, low dose administration also leads to the stimulation of regulatory T cells. Monoclonal antibodies and bispecific killer engagers (BiKEs) may enhance specificity by targeting CD16 on NK cells to tumor antigens. Inhibition of CD16 shedding may also promote enhanced cytotoxicity. Future strategies include exploiting favorable donor immunogenetics or ex vivo expansion of NK cells from blood, progenitors, or pluripotent cells. Comparative clinical trials are needed to test these approaches.