The endoplasmic reticulum (ER) is a cellular compartment specialized for chaperone-assisted folding and post-translational modification of nascent polypeptides. Protein folding in the complex environment of the ER is unique because oxidizing conditions promote formation of disulfide bonds. Disulfide bond formation is coupled with production of reactive oxygen species, ie. oxidative stress. Disruption of ER homeostasis through increased biosynthetic load, alteration in the oxidizing conditions, reduction in calcium storage, energy depletion, or expression of folding incompetent proteins leads to accumulation of unfolded protein and activation of the unfolded protein response (UPR). The UPR emanates from the ER through activation of three transmembrane sensors, IRE1, ATF6, and PERK. IRE1 is a protein kinase that has an endoribonuclease (RNase) activity that initiates a site-specific unconventional splicing reaction that removes a 26b intron within the XBP1 mRNA. Spliced XBP1 mRNA produces a potent basic leucine zipper (bZiP)-containing transcription factor of the ATF/CREB family that activates UPR gene transcription. ATF6 is a type II ER transmembrane protein that contains a bZiP domain in the cytosol and a stress-sensing domain in the ER lumen. Upon accumulation of unfolded proteins in the ER lumen, ATF6 transits to the Golgi compartment where it is cleaved by the proteases S1P and S2P to generate the cytosolic fragment that transits to the nucleus to activate transcription of a subset of UPR genes. Finally, activation of PERK by ER stress leads to inhibition of translation initiation through phosphorylation of eukaryotic initiation factor 2 (eIF2) on the alpha subunit. Paradoxically, there are several mRNAs that require eIF2α phosphorylation for efficient translation, for example, ATF4 mRNA. ATF4 encodes a transcription factor required to activate genes involved in protein folding, anti-oxidative stress responses, and amino acid biosynthesis and transport. If the adaptive UPR cannot resolve the protein-folding defect, cells enter apoptosis. ER stress-induced apoptosis is primarily mediated through ATF4-mediated transcriptional induction of the C/EBP homologous protein CHOP. Studies will be summarized that demonstrate the unique and essential features of the cellular response to ER stress and how ER stress is intimately coupled with oxidative stress. For example, glucose-regulated insulin production in pancreatic beta cells requires an intact PERK/eIF2α subpathway to prevent oxidative stress. Either increases in protein synthesis or accumulation of misfolded protein in the ER leads to oxidative stress and apoptosis. Studies will be summarized that demonstrate anti-oxidants can improve protein folding in the ER and prevent cell death. Studies will show how mouse models can be used to dissect the roles of the UPR subpathways in different physiological and pathological conditions.