Gene-targeting technology in embryonic stem cells has allowed creation of animals transgenic or mutant for a number of molecules. The presence of spontaneous chronic intestinal inflammation in mice mutant for interleukin-2, interleukin-10, and T-cell receptor genes has provided new models of chronic intestinal inflammation. By crossing mice mutant for different genes with each other, it is possible to generate mice deficient for a group of specific cytokines, adhesion molecules, or lymphocyte subsets. These models will not only help clarify the role of factors considered important in the pathogenesis of chronic intestinal inflammation, but they also permit precise dissection of mucosal immune responses and may help develop new therapeutic approaches to human inflammatory bowel disease.