All cells must balance the production of proteins and lipids to maintain membrane functions. Imbalances in protein folding and lipid metabolism cause endoplasmic reticulum (ER) stress, which is associated with a wide range of complex diseases including diabetes and neurodegeneration. The central homeostatic program of the ER is the unfolded protein response (UPR), which senses accumulating unfolded proteins to control global protein synthesis, chaperone abundance, and lipid metabolism. Through these mechanisms, the UPR centrally controls decisions between cell survival, adaptation, and apoptosis. We have shown that perturbations of the cellular lipidome, referred to as lipid bilayer stress, are equally potent as unfolded proteins in activating the UPR. Using an interdisciplinary platform to study highly flexible membrane property sensors, we could found that an aberrant stiffening of the ER membrane is sufficient to activate the UPR by driving the sensor protein Ire1 into oligomers via a hydrophobic mismatch-based mechanism. On the basis of these findings, we are seeking to identify the molecular signatures and physical principles underlying of a chronic activation of the UPR. We show that chronic ER stress can be initiated and maintained by a membrane-based mechanism: Ire1 perpetuates a vicious cycle, which leads to an accumulation of saturated lipids, massive changes of ER morphology, and dramatically increased rates of cell death. This vicious cycle can be interrupted by a single point mutation in the transmembrane domain of Ire1 thereby restoring ER morphology and cellular fitness. Together, we provide a radically new, membrane-based perspective on the role of the UPR in acute and chronic ER stress.