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Over the past few years, application of targeted gene deletion and transgenic approaches has led to the often unanticipated development of rodent lines which develop inflammatory bowel disease. While none of these lines recapitulate the histopathological and clinical features usually associated with human inflammatory bowel disease (IBD) in their entirety, many exhibit key features comprising the development of "spontaneous" chronic and acute inflammation. These models include targeted deletion of the genes encoding IL-2, IL-10, TGF beta, T-cell receptor alpha/beta, keratin 8, and Gi2 alpha. In addition, animals expressing transgenes for the human WA-B27 (with beta-2 microglobulin) as well as a dominant negative construct which functionally blocks N-cadherin have also been observed to result in chronic inflammatory bowel disease. Most of the mutant murine lines experience a diffuse colitis, but some (HLA-B27 transgenic and IL-10-deficient) also experience small bowel inflammation. The variety of manipulations provides some important broad insights: (1) IBD can result from dysregulation of mucosal immune responses or impairment of epithelial barrier function, and (2) the natural history of inflammation resulting from mutation at a single genetic loci is substantially modulated by other genetic factors. With the rapidly-increasing variety of mutant mice, comparison of the residual components of immune system in lines developing IBD with those of lines not developing IBD, it is possible to deduce a requirement for TCR gamma/delta CD4+ lymphocytes as well as pivotal role of IFN gamma and (as a suppressive factor) IL-10. Study of a number of models has demonstrated the important interaction between environmental factors and genetic predisposition. Thus, in at least some of the lines (IL-2-deficient and HLA-B27) the inflammatory bowel disease is not observed when the mutant mice are maintained in a germ-free environment but does develop after reconstitution with a pathogen-free flora. In the TCR alpha/beta deficient mice, appendectomy in the neonatal period prevents the subsequent development of colitis. In still other models, inflammation may not occur without some challenge by an exogenous external agent, e.g., mice deficient in intestinal trefoil factor (ITF) exposed to dextran sodium sulfate (1). These models offer great promise to permit further dissection of the various constituents of the intestinal epithelium and mucosal immune response systems which are necessary for maintaining normal homeostasis and which can contribute to the development of inflammatory bowel disease. Further, they offer powerful tools for exploring the interaction between genetic and environmental factors to explicate the pathogenesis of inflammatory bowel disease and to develop new therapeutic intervention strategies.