The unfolded protein response (UPR) is a collection of intracellular pathways that function to maintain homeostasis in the ER. The mammalian UPR is distinguished by three ER-resident transmembrane proteins–PERK, ATF6 and IRE1–that serve as the UPR’s proximal sensors. When ER functions are perturbed, these sensors initiate several responses that activate a number of signaling pathways. These pathways can result in homeostasis or apoptosis. One crucial issue that remains unclear is how cells interpret signals sent by the UPR to make cell-fate decisions, such as whether to adapt or whether to commit to apoptosis.