When protein folding in the endoplasmic reticulum (ER) is disrupted by alterations in homeostasis in the ER lumen, eucaryotic cells activate a series of signal transduction cascades that are collectively termed the unfolded protein response (UPR). Here we summarize our current understanding of how the UPR functions upon acute and severe stress. We discuss the mechanism of UPR receptor activation, UPR signal transduction to translational and transcriptional responses, UPR termination, and UPR signals that activate upon irreversible damage. Further, we review recent studies that have revealed that UPR provides a wide spectrum of physiological roles. Each individual UPR subpathway provides a unique and specialized role in diverse developmental and metabolic processes. This is especially observed for professional secretory cells, such as plasma cells, pancreatic beta cells, hepatocytes, and osteoblasts, where high-level secretory protein synthesis requires a highly evolved mechanism to properly fold, process, and secrete proteins. There is a growing body of data that suggest that different subpathways of the UPR are required throughout the entire life of eucaryotic organisms, from regulation of differentiation to induction of apoptosis.