As more cancer patients survive their disease, concerns about radiation 
therapy-induced side effects have increased. The concept of radioprotection and 
radiation injury mitigation and treatment offers the possibility to enhance the 
therapeutic ratio of radiation therapy by limiting radiation therapy-induced 
normal tissue injury without compromising its antitumor effect. Advances in the 
understanding of the underlying mechanisms of radiation toxicity have stimulated 
radiation oncologists to target these pathways across different organ systems. 
These generalized radiation injury mechanisms include production of free 
radicals such as superoxides, activation of inflammatory pathways, and vascular 
endothelial dysfunction leading to tissue hypoxia. There is a significant body 
of literature evaluating the effectiveness of various treatments in preventing, 
mitigating, or treating radiation-induced normal tissue injury. Whereas some 
reviews have focused on a specific disease site or agent, this critical review 
focuses on a mechanistic classification of activity and assesses multiple agents 
across different disease sites. The classification of agents used herein further 
offers a useful framework to organize the multitude of treatments that have been 
studied. Many commonly available treatments have demonstrated benefit in 
prevention, mitigation, and/or treatment of radiation toxicity and warrant 
further investigation. These drug-based approaches to radioprotection and 
radiation injury mitigation and treatment represent an important method of 
making radiation therapy safer.