There are now many experimental models of inflammatory bowel disease (IBD), most of which are due to induced mutations in mice that result in an impaired homeostasis with the intestinal microbiota. These models can be clustered into several broad categories that, in turn, define the crucial cellular and molecular mechanisms of host microbial interactions in the intestine. The first of these components is innate immunity defined broadly to include both myeloid and epithelial cell mechanisms. A second component is the effector response of the adaptive immune system, which, in most instances, comprises the CD4⁺ T cell and its relevant cytokines. The third component is regulation, which can involve multiple cell types, but again particularly involves CD4⁺ T cells. Severe impairment of a single component can result in disease, but many models demonstrate milder defects in more than one component. The same is true for both spontaneous models of IBD, C₃H/HeJBir and SAMPI/Yit mice. The thesis is advanced that ‘multiple hits’ or defects in these interacting components is required for IBD to occur in both mouse and human.