There is now considerable evidence that abnormalities of the structure and function of the colonic epithelium are present in patients with ulcerative colitis and that many of these may occur independently of mucosal inflammation. It is proposed that epithelial abnormalities are the central defect that underlie the development of mucosal inflammation and its chronicity. A simple model for pathogenesis is proposed in which inflammation develops only when epithelial barrier function is impaired to an extent which permits the influx of luminal pro-inflammatory molecules to the lamina propria. Several candidate hypotheses regarding the molecular basis for the abnormality are addressed. The mechanism by which the barrier function is critically impaired involves the interaction of the abnormal epithelium with luminal, mucosal and systemic factors. Focusing on the epithelium would potentially lead to a conceptually different management approach and the development of novel therapeutic strategies.