New research provides a mechanism that links autophagy and the endoplasmic reticulum (ER) stress response with Crohn's disease, and suggests that Paneth cells are the origin of inflammation in the intestines. Mice that were unable to mount an ER stress response in intestinal epithelial cells (IECs) showed increased autophagy induction, most notably in Paneth cells. Conversely, mice with an IEC autophagy defect had evidence of ER stress and inflammation. The absence of both pathways in IECs or specifically in Paneth cells led to severe ileitis that depended on commensal bacteria and that resulted from increased IEC death. Mechanistic studies indicate that the failure to remove ER stress-induced activated inositol-requiring enzyme 1α (IRE1α) by autophagy promotes inflammation through nuclear factor-κB activation and tumour necrosis factor signalling.