Significance: Ionizing radiation (IR) is an effective and commonly employed treatment in the management of more than half of human malignancies. Because IR's ability to control tumors mainly relies on DNA damage, the cell's DNA damage response and repair (DRR) processes may hold the key to determining tumor responses. IR-induced DNA damage activates a number of DRR signaling cascades that control cell cycle arrest, DNA repair, and the cell's fate. DNA double-strand breaks (DSBs) generated by IR are the most lethal form of damage, and are mainly repaired via either homologous recombination (HR) or nonhomologous end-joining (NHEJ) pathways. Recent Advances: In recent years, immense effort to understand and exploit the differences in the use of these repair pathways between tumors and normal cells will allow for an increase in tumor cell killing and a decrease in normal tissue injury. Critical Issues: Regulation of the two major DSB repair mechanisms (HR and NHEJ) and new strategies, which may improve the therapeutic ratio of radiation by differentially targeting HR and NHEJ function in tumor and normal tissues, is of intense interest currently, and is the focus of this article. Future Directions: By utilizing the strategies outlined above, it may be possible to exploit differences between tumor and somatic cell DRR pathways, specifically their DSB repair mechanisms, to improve the therapeutic ratio of IR. Antioxid. Redox Signal. 21, 251–259.