Natural killer (NK) cells are innate immune lymphocytes that are identified by the expression of the CD56 surface antigen and the lack of CD3. Unlike antigen specific T cells, NK cells do not require the presence of a specific tumor antigen for the recognition and killing of cancer cells. Our in vitro studies have demonstrated that pretreatment of malignant cells with bortezomib significantly enhances NK-mediated tumor cytotoxicity by sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL). TRAIL is a member of tumor necrosis factor family of cytokines that promotes apoptosis. Importantly, in our laboratory, in vitro expanded NK cells isolated from patients with metastatic cancers or hematological malignancies exhibited significantly more cytotoxicity against their tumor cells when tumors were pre-treated with bortezomib compared with untreated tumor controls. These findings suggest that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate anticancer effects of autologous adoptively infused NK cells in patients with cancer.