Pazopanib, (GW786034B, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide), a novel and potent vascular endothelial growth factor receptor inhibitor , is a small-molecule inhibitor shown to target both tumor and endothelial cells in multiple myeloma . Pazopanib targets the TKRs including VEGFR-1/2/3, PDGFRα/β, and c-KIT . Pre-clinical studies have shown that Pazopanib can inhibit tumor angiogenesis and the growth of several human tumor xenografts (multiple myeloma, colon, melanoma, prostate, kidney) in mice . In addition, in 2009 Pazopanib was approved by the US FDA for the treatment of patients with advanced renal cell carcinoma (RCC). Additionally, several recent phase II and III studies have shown a significant clinical benefit of Pazopanib in a variety of malignancies, including soft tissue sarcoma, thyroid cancer, and ovarian cancer [21–23]. In the current study we tested the curative potential of a combination of SDRT with Pazopanib on xenografts of human sarcoma tumors, a chondrosarcoma (JJ012) and a neurofibrosarcoma (MPNST3). Our results revealed that a single dose of Pazopanib mimics the anti-VEGF/VEGFR impact on tumors subsequently exposed to SDRT, increasing ASMase activity in the serum and tumor endothelial dysfunction, enhancing tumor response, and exhibiting critical dependence on timing relative to SDRT exposure. These results suggest that Pazopanib has a similar mechanism of action to the one we previously demonstrated for anti-VEGF/VEGFR2 antibodies. As a short-acting anti-angiogenic, Pazopanib might be optimal for endothelial-mediated radiosensitization, and in combination with SDRT it might allow dose de-escalation, thus significantly expanding the range of clinical indications for SDRT.