As one of the potent and efficient cancer therapies, radiation is widely used to treat a variety of cancer types. Ionizing radiation (IR) works by damaging the DNA of normal and cancerous tissue leading to cellular death . The goal of radiation therapy (RT) is to maximize damage to cancer cells while keeping collateral damage to a minimum [1, 2]. Studies in this field revealed that IR-induced DNA damage repair is more efficient in normal cells than in tumor cells, which display dysregulated repair . Standard RT protocols for cancer patients use a low dose (1.8–2.0 Gy) exposure repeated daily until the maximal tolerable normal tissue doses are reached. Given that the total dose delivered to tumors is generally determined by normal tissue toxicity rather than by the curable dose required for tumor eradication, the overall local cure using fractionated approach is ~65% of all tumors, and curability depends on tumor type and size. Following the development of intensity modulation RT (IMRT) and image guidance RT (IGRT), which can improve precision in tumor targeting and reduce normal tissue exposure, SDRT is gradually becoming an alternative therapeutic strategy. SDRT has shown clinical benefit with local control rates at over 90% in a variety of cancer types, including tumors considered resistant to conventional fractionated RT [3, 4]. Although SDRT presents a practical alternative approach for fractionated radiotherapy, its biological mechanism remains elusive. We recently reported that SDRT induces a rapid wave of endothelial cell apoptosis via ceramide generation in both normal gastrointestinal tract and tumors [5–7]. In this regard, SDRT launches a rapid translocation of acid sphingomyelinase (ASMase) to the endothelial plasma membrane, where ASMase converts sphingomyelin to the second messenger ceramide and the latter mediates apoptotic signaling [8, 9]. The 20-fold enrichment of a non-lysosomal secretory form of ASMase results in endothelial cells being particularly vulnerable to radiation-induced ASMase-mediated generation of the pro-apoptotic second messenger ceramide [10–12]. Importantly, our previous studies showed that the angiogenic factors bFGF or VEGF restrain radiation-induced ASMase activation, ceramide generation, and consequent endothelial apoptosis [12, 13]. Conversely, anti-angiogenic agents, such as anti-VEGFR2 antibody, antagonize these effects, synergistically increasing radiation-induced ceramide elevation and enhancing apoptosis . Furthermore, in vivo these agents cause a synergistic increase in radiation-induced tumor endothelial apoptosis and enhanced tumor response to SDRT . These studies therefore define that an ASMase/ceramide pathway-dependent endothelial response plays a crucial role in tumor cure by SDRT and is modulated by angiogenic factors.