The identification of the early events occuring in ulcerative colitis may lead to a better understanding of the etiology of this disease. Many observations have now indicated that colonic epithelial abnormalities occur independently of the presence of mucosal inflammation and have suggested that early events are more likely to involve the epithelium than immuno-inflammatory mechanisms. Although a large number of candidate luminal and mucosal mechanisms for injuring the epithelium or modulating its function can be identified, the real reasons why the epithelium is abnormal remain unclear. Mucosal inflammation may well be a secondary phenomenon due to influx into the lamina propria of luminal macromolecules with toxic, antigenic, immunoadjuvant and chemoattractant properties. This pathogenic model offers new areas of focus for research and the potential for novel therapeutic approaches.