The intestine is often dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of long-term cancer survivors. Of the 8 to 9 million cancer survivors currently living in the United States, more than half have had abdominal or pelvic tumors, and about 60% of these patients have undergone or will undergo radiation therapy. Therefore, interventions that limit postradiation intestinal dysfunction would significantly improve outcomes in a large number of patients. Worthwhile steps toward reducing toxicity of treatments have been taken recently by introducing dose-sculpting treatment techniques. However, prophylactic or therapeutic approaches derived from an improved understanding of the pathophysiology of bowel injury will result in further advances. This article reviews current principles in the diagnosis and management of intestinal radiation injury. It also provides an overview of investigational strategies aimed at reducing radiation-induced bowel toxicity. These strategies include free radical scavengers, antioxidants, cytoprotective agents, cytokines, and enterotrophic interventions, as well as modulators of intraluminal factors, endothelial dysfunction, and neuroimmune interactions. Preclinical testing in clinically relevant animal models will facilitate translation of these strategies into the clinic and contribute to improving cancer cure rates and quality of life in cancer survivors.