Radiotherapy frequently results in persistent effects on gastrointestinal function adversely impacting on the quality of life of patients cured of their malignant disease. Long-term effects on gastrointestinal function remain prevalent despite the advent of three-dimensional techniques of radiotherapy because higher radiation doses and more combined modality treatments are prescribed to improve cure rates. Chronic elevation of cytokine levels and implication of the cyclooxygenase-2 pathway in radiation bowel injury in animals, and the involvement of the Rho/Rho kinase pathway in the fibrogenic differentiation of smooth muscle cells of patients with late radiation enteritis, suggest a role for inhibition of these pathways. The importance of limiting acute gastrointestinal toxicity by dietary, pharmacological and physical interventions and of optimizing radiotherapy techniques and prescriptions is underscored by increasing evidence that a component of the long-term effects of radiotherapy on gastrointestinal function is a consequence of acute damage. Strategies to control acute toxicity are important in reducing the impact of long-term effects of radiotherapy on gastrointestinal function. Further research into genetic profiling to characterize individual risk of radiation bowel damage and the pathways implicated in fibrogenic differentiation is needed to reduce and prevent bowel complications.