Stress induced by accumulation of misfolded proteins in the endoplasmic reticulum (ER) is observed in many physiological and pathological conditions. To cope with ER stress, cells activate the unfolded protein response (UPR), a dynamic signaling network that orchestrates the recovery of homeostasis or triggers apoptosis, depending on the level of damage. Here we provide an overview of recent insights into the mechanisms cells employ to maintain proteostasis and how the UPR determines cell fate under ER stress.