Products of the IRE1 genes, which are conserved from yeast to mammals, respond to the accumulation of unfolded proteins in the endoplasmic reticulum and mediate the so-called ER stress response, by which chaperone proteins are induced and targeted to the ER. This pathway, mediated in most cells by the ubiquitously expressed Ire1a protein, is essential for mouse development but the related protein Ire1b has not been carefully studied. Bertoletti and colleagues have now generated mice lacking this isoform, which prove to be grossly normal and fertile (okay?). Taking a cue from the highly restricted expression of Ire1b, which is found in the stomach and intestines, the authors examined the mutant mice for a defect in the GI tract. The gastric epithelium appears normal in Ire1b-/-animals but is hypersensitive to the effects of dextran sodium sulfate (DSS), an irritant that induces the ER stress response and provokes symptoms of inflammatory bowel disease in mice. Epithelial cells in mutant mice have higher baseline levels of the ER resident chaperone protein BiP and of the protective MAP kinase pathway, which acts in both the unfolded protein response in the ER and in similar cytoplasmic pathways, as expected if the absence of Ire1b is required for homeostasis in response to increased levels of unfolded proteins in the secretory pathway. Evidently, Ire1a and other sensors proteins can activate some aspects of the normal unfolded protein responses, but they are not sufficient to protect the cells from damage in the absence of Ire1b.