Mammals are highly adapted to their very high densities of non-pathogenic bacteria which inhabit the lower small intestine and colon. This is achieved by a series of functional and cellular layers that normally avoid the inflammatory consequences of immune activation by bacterial molecules. In this review we set out the layers of mucosal immune defence to show the many ways in which mutualism with the commensal flora can break down to trigger chronic intestinal inflammation in animal models and inflammatory bowel disease (IBD) in humans.