Experimental model data strongly support the immunologic hypothesis of IBD pathogenesis. Critical genes, molecules and pathways maintaining intestinal homeostasis with the microbiota are being defined. Epithelial cell mutations can result in pathogenic adaptive immune responses to the microbiota and IBD. Innate, adaptive and regulatory immune defects can result in IBD. Multiple different mutations and mechanisms can result in experimental colitis with a similar histopathology. © 2010 Blackwell Publishing Ltd.