Radiotherapy is a common cytotoxic treatment for solid tumors. While the primary goal of radiation-drug combinations is to increase the efficacy of destroying tumor cells, it is also vital to lower the toxicity to normal tissue because the effectiveness of therapy is dependent on the difference between efficacy and toxicity. Radiotherapy-induced DNA damage regulates cell proliferation and modifies the cell cycle, eventually triggering apoptosis or additional programmed death pathways. The molecular pathways of reactions to DNA damage are reviewed, with an emphasis on repair mechanisms, therapeutic targets now being studied in clinical trials, and prospective novel targets. A deeper understanding of the DNA damage responses (DDR's) molecular processes, as well as the genetic linkages between the DDR pathways and other cellular pathways, will lead to new treatment possibilities for a number of human disorders, including cancer.