Study of the unfolded protein responses (UPR) is mainly addressed by challenging eukaryotic cells with chemical compounds that impair calcium, redox or glycan homeostasis. These dramatically alter the endoplasmic reticulum (ER) environment and function, but also trigger pleiotropic effects that may result in multi-organellar failure and cell death. Recent works showed that UPR induced by the accumulation of unfolded polypeptides in the ER lumen drastically differs from chemically induced UPR. Unfolded proteins are tolerated by cells, which activate a finely tuned UPR without entering apoptotic programs. How cells adapt the UPR to the burden of misfolded proteins, what structural features of the accumulating proteins determine UPR intensity and how these mechanisms translate into disease are crucial questions to be address in the future.