The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) γ agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.