Radiation therapy remains one of the most effective cancer treatments. Nevertheless, biology-driven personalized radiation therapy that enables treatment according to the biological characteristics of the individual tumors and normal tissues still needs to be implemented in the clinic. Understanding the mechanisms of radiation response in both tumors and normal tissues is necessary to develop reliable predictive biomarkers for tumor radioresistance and normal tissue toxicity as well as to exploit new therapeutic opportunities for tumor radiosensitization. In this article, we review the mechanisms of tumor radiosensitivity as well as the early and late responses of normal tissues to therapeutic radiation exposure. We also discuss the possible implementation of these mechanisms for biology-driven personalized radiation treatment.