Although tumor antigen-specific immunotherapy, such as dendritic cell vaccine, has recently emerged as a promising clinical approach, one limitation of tumor antigen- and T-cell receptor (TcR)-specific immunotherapy is antigen-specific inhibition by antigen-specific regulatory T-cell and myeloid suppressor cells. Therefore, immunotherapy using a TcR-independent mechanism may be an alternative immunotherapeutic strategy. NKG2D (natural killer, group 2, member D) and DNAX accessory molecule-1 (DNAM-1) are both activated receptors that are strongly expressed on T-cells, γδT-cells, and NK cells. Therefore, the expression of ligands for NKG2D and DNAM-1 on tumor cells plays an important role in tumor opsonization by immune effector cell targeting. Various modulatory methods for up-regulating NKG2D and DNAM-1-ligands have been reported, and included chemotherapeutic agents and hyperthermia. Although there are many obstacles to the utilization of NKG2D and DNAM-1 for cancer therapy, combined treatments using immune cell therapy and chemotherapy that take advantage of NKG2D and DNAM-1 may be an ideal approach.