Radiotherapy is an important part of modern cancer management for many malignancies, and enhancingthe radiosensitivity of tumor cells is critical for effective cancer therapies. The Notch signaling pathway playsa key role in regulation of numerous fundamental cellular processes. Further, there is accumulating evidencethat dysregulated Notch activity is involved in the genesis of many human cancers. As such, Notch inhibitorsare attractive therapeutic agents, although as for other anticancer agents, they exhibit significant and potentialside effects. Thus, Notch inhibitors may be best used in combination with other agents or therapy. Herein, wedescribe evidence supporting the use of Notch inhibitors as novel and potent radiosensitizers in cancer therapy.