The etiology and pathogenesis of inflammatory bowel disease (IBD) remains unsolved but improved experimental models of enterocolitis have led to progress. Intestinal inflammation can be induced by chemical or dietary factors or by microbial products and experimental IBD. Many animal models of IBD can be used to evaluate new anti-inflammatory drugs. These models, however, usually demonstrate acute, self-limiting colitis. The spontaneous colitis models developed in the monkey, cotton-top tamarin, and C3H/HeJBir mouse mimic more features of human IBD. Inflammation is chronic and is under genetic control. The differential genetic susceptibility of inbred rat strains to chronic inflammation have been exploited. Lewis rats injected with bacterial products, peptidoglycan polysaccharide or indomethicin develop chronic relapsing enterocolitis, whereas closely related Buffalo or Fisher rat strains develop only transient inflammation and the specific inhibition of inflammatory mediators and target molecules have been tested. Over-expression (transgenic) or deletion (knockout) of specific genes have led to the development of rodent models of spontaneous colitis. Inflammation arises from a number of mutations of immunomodulatory molecules supporting the concept of genetic heterogeneity for IBD. The results obtained from experimental models have generated new hypotheses, expanded human studies, and suggested novel forms of therapy for IBD patients.