Renewal of the gastrointestinal (GI) epithelium fulfills the normal functions of maintaining the integrity of the mucosa, repairing mucosal injury, and replenishing the specialized cells of the epithelium. Alterations in epithelial renewal also are intimately involved in transformation of the epithelium to benign and malignant neoplasms. Certain abnormalities in epithelial proliferation, including an increase in the rate of proliferation and expansion of proliferating cells beyond the normal zone of proliferation, are closely linked to the predisposition for and frank development of GI cancer. These abnormalities are common to all human premalignant conditions studied, including Barrett's epithelium, chronic gastritis, inflammatory bowel disease, and colon polyps; they also occur in experimental carcinogenesis. The same proliferative abnormalities have also been observed in some relatives of patients with colon neoplasms who themselves do not have any colon polyps or cancer. Several agents, including calcium, vitamins A, C, and E, and omega-3 fatty acids, have been shown to reverse the abnormal proliferation under some laboratory and clinical conditions. Moreover, some nonsteroidal anti-inflammatory drugs appear to decrease the size of colon polyps in familial polyposis and to reduce the risk for colon cancer in the general population. We await further clinical trials that will indicate whether such ordinary supplements as calcium, vitamins, fish oil, or aspirin have a role in the treatment of patients with premalignant conditions of the gastrointestinal tract.