Radioprotectors are agents that protect against radiation injury when administered prior to radiation exposure. Mitigators are agents that can protect against radiation injury when given after exposure but before any symptoms appear. Because of concern on a mass casualty situation due to accidental exposure to radiation (e.g., Fukushima and Chernobyl nuclear reactor disaster) or intentional exposure (e.g., nuclear device or “dirty bomb”), development of novel radioprotectors and particularly mitigators (called “radiation countermeasures”) is currently a high priority. As radioprotectors and mitigators can potentially improve the outcomes of radiation therapy for cancer treatment (e.g., by allowing higher doses of radiation and/or reduced damage to normal tissues), there is an interest in whether there is a role for some of these novel agents in the radiotherapy clinic. The applicability of these agents to the cancer clinic is critically dependent on whether or not they will also render tumors more resistant to radiation, which, in turn, relates to their biochemical and biological mechanism(s) of action. Here, we will review what has been learned during the development of these protectors and mitigators on the molecular mechanisms leading to radiation injury, the proposed radioprotective agents that have been developed, and the molecular pathways that can lead to radioprotection and mitigation.