This chapter discusses various models and the factors that can lead to inflammatory bowel disease. Murine colitis models mimic enough aspects of human inflammatory bowel disease (IBD) to enable investigators to study immunological pathways and test novel therapies. The mechanism by which infliximab suppresses Crohn's disease (CD) is different from the absorption of free tumor necrosis factor (TNF) in mice. These findings illustrate that immune pathways originally discovered in murine colitis may lead to human therapies, even though the underlying mechanisms need not necessarily be similar. On the basis of their potent immunosuppressive effects in mice, reagents directed against IL-6, IL-18, and MIF form possible future therapies. In contrast to CD28 and CD154, GITR and CD134 are particularly interesting targets for the modulation of IBD. The variation in immune-stimulating capability among organisms extends to their antigens. The isolation and identification of a limited set of microbial antigens driving disease in C3H/HeJBir mice, with use of serologic expression cloning confirm that that there are not only immunodominant organisms but also a limited set of immunodominant antigens recognized by the host immune system. © 2005 Elsevier Inc. All rights reserved.