Advances in cancer immunotherapy are leading to its increasing and successful application for the treatment of solid-tissue cancers. Despite the recent advances there are still significant barriers, in particular, evidence for significant tumor heterogeneity, both genetic and epigenetic that limit long-term efficacy. Subpopulations of "stem-like" tumor cells have been identified in nearly all human malignancies based on both morphologic and functional criteria. Also called cancer stem cells or CSCs, these quiescent cells display enhanced tumorigenic potential and are capable of repopulating tumors in the wake of traditional cytoreductive therapies. These CSCs may be best targeted via immunotherapy. Our lab has identified activated natural killer (NK) cell-based therapy as an effective method to target CSCs particularly after radiation therapy for solid tumors. Using a variety of in vitro and in vivo methods, including the utilization of primary tumor tissue and patient-derived xenografts, we observed that autologous and allogeneic NK cells possess the ability to preferentially kill stem-like cells or CSCs from freshly isolated patient samples representing a broad spectrum of tumor types, including pancreatic cancers, breast cancers, and sarcomas. The results indicated that CSCs express stress ligand molecules capable of being targeted by NKG2D on NK cells and that prior radiation therapy can both deplete the cycling non-CSCs bulk tumor population and upregulate these stress ligands on the CSC making this an effective combination approach.