In this study, we evaluated the role of tumor cell and tumor stroma sensitivity as determinants of radiation-induced tumor growth delay. A DNA double-strand break repair–defective DNA-PKcs^−/− tumor cell line and its radioresistant DNA-PKcs^+/+–transfected counterpart were used to initiate tumors in nude and hypersensitive severe combined immunodeficient (SCID) mice. Insertion of the human DNA-PKcs^+/+ gene substantially increased the intrinsic radioresistance of the DNA-PKcs^−/− tumor cells and substantially decreased tumor response to radiation in both nude and hypersensitive SCID mice. Tumor cell radiosensitivity was the major determinant of tumor response in nude mice. In SCID mice, both tumor cell sensitivity and radiation-induced stromal damage contributed to response. The relative contribution of host and tumor cell sensitivity on tumor response was unchanged for single doses of 1 × 15 and 6 × 3 Gy–fractionated dose irradiation. [Cancer Res 2007;67(9):4015–21]