Oxidative protein folding (OPF) characterized by intramolecular disulfide bond formation is the most common and likely most ancient post-translational modification. Considering the number of proteins that a cell must fold correctly and the number of possible disulfide structures available to each protein, OPF represents a daunting biochemical permutation problem which is solved by relatively few oxidase and isomerase enzymes. A proper disulfide configuration provides the structural foundation for more nuanced intramolecular folding events that, ultimately, define protein activity. As such, control of OPF is critical to normal cell function and homeostasis. Ironically, when cells are stressed, the very process of OPF can generate reactive oxygen species, contributing to endoplasmic reticulum stress, inefficient protein folding, and initiation of the unfolded protein response-a phenomenon that induces pro-inflammatory signals which can contribute to metabolic and inflammatory diseases, neurodegenerative disease, and cancer. Contributing authors to this Forum of Antioxidants and Redox Signaling review the latest developments in our understanding of the complex and divergent processes that orchestrate OPF. New insights promise to offer improvements in both medicine and industrial biotechnology.