A number of models of spontaneous chronic intestinal inflammation in mice and rats have recently been developed. A characteristic of the majority of these models is that disease developed as a consequence of immune manipulations, suggesting a central role for the immune system in the regulation of intestinal inflammation. Analysis of cytokine patterns in disease showed elevations in TNF-alpha and IFN-gamma, characteristic of the T-helper-1 (Th1) pathway, implicating Th1 cells and their cytokines in disease pathogenesis. Strikingly, inflammation did not develop in mice maintained in germ-free conditions, suggesting disease may develop due to a dysregulated inflammatory response to components of the normal flora. Evidence from a number of these models suggests that this potentially pathogenic inflammatory response does not develop in normal animals as it is actively inhibited by a population of CD4+ alpha beta + regulatory T cells and immunosuppressive cytokines such as IL-10 and TGF-beta 1. These new models will allow further investigation into the mechanisms of natural immune regulation and protection in the intestinal tract and how these mechanisms relate to the etiopathogenesis of inflammatory bowel disease (IBD). Furthermore, these models should provide useful insights for the design of effective immunomodulatory therapies for the treatment of IBD in humans.