All eukaryotic cells possess an endoplasmic reticulum (ER), which is the site for synthesizing proteins that populate the cell surface or extracellular space. The environment of the ER is oxidizing, which supports the formation of intra- and interchain disulfide bonds that serve to stabilize the folding and assembly of nascent proteins. Recent experimental data reveal that the formation of disulfide bonds does not occur spontaneously but results from the enzymatic transfer of disulfide bonds through a number of intermediate proteins, with molecular oxygen serving as the terminal electron acceptor. Thus, each disulfide bond that forms during oxidative folding should produce a single reactive oxygen species (ROS). Dedicated secretory tissues like the pancreas and plasma cells have been estimated to form up to 3-6 million disulfide bonds per minute, which would be expected to result in the production of the same number of molecules of ROS. Although the methods used to deal with this amount of oxidative stress are not well understood, recent research suggests that different types of cells use distinct strategies and that the unfolded protein response (UPR) is a critical component of the defense.