Despite constant progress in radiotherapy techniques such as tumour imaging and cartography, techniques of radiation delivery or fractionation schedules, damage to normal gastro-intestinal tissues is inevitably associated with radiation therapy of pelvic tumours. Acute radiation enteritis concerns 80% of patients. It is related to stem cell loss, default in epithelial regenerating capacity and inflammation-induced mucosal dystrophy and ulceration. Chronic injury may develop in 5 to 10% of patients and is characterized by intestinal wall fibrosis resulting from an exaggerated scarring process, chronic inflammation and tissue necrosis. Research in mechanistic processes of normal tissue damage paved the way for new therapeutic approaches to emerge. These new targets include mucosal regeneration, reduction of vascular activation, inflammation and thrombosis, and fight against mesenchymal cells sustained activation. Effective strategies are multiple on preclinical models, but numerous efforts have to be made to achieve the complicated goal of protection of normal tissues from the side effects of radiation therapy.