Stereotactic body radiation therapy in which a large radiation dose is delivered with each daily treatment to a tumor target can markedly improve local control, but the mechanism by which high-dose radiation therapy (RT) improves tumor cure has been controversial. Using genetically engineered mouse models of sarcoma and lung cancer, specific cellular compartments (tumor cells vs. endothelial cells) were radiosensitized to characterize the impact on tumor response to high-dose RT. While radiosensitization of tumor endothelial cells increased endothelial cell death and vascular dysfunction, the tumors still recurred following RT. By contrast, radiosensitization of tumor parenchymal cells (depicted in the schematic) directly enhanced radiation-induced growth delay of lung cancers and increased tumor cure of sarcomas. For details, see the article by Castle and Kirsch on page 5685.