Significance: High levels of reactive oxygen species can facilitate DNA and protein damage beyond the control of endogenous antioxidants, resulting in oxidative stress. Oxidative stress then triggers inflammation, which can lead to pathological conditions. In genetically susceptible individuals, the conglomeration of oxidative stress and inflammation can enhance autoreactive immune cell activation, causing beta-cell destruction in autoimmune type 1 diabetes. As a means of shielding pancreatic islets, manganese porphyrin (MnP) oxidoreductant treatment has been tested in a number of reported studies. Recent Advances: MnP affects both innate and adaptive immune cell responses, blocking nuclear factor kappa-B activation, proinflammatory cytokine secretion, and T helper 1 T-cell responses. As a result, MnP treatment protects against type 1 diabetes onset in nonobese diabetic mice and stabilizes islets for cellular transplantation. Critical Issues: MnP displays global immunosuppressive properties, exemplified by decreased cytokine production from all T-helper cell subsets. This quality may impact infection control in the setting of autoimmunity. Nonetheless, because of their cytoprotective and immunomodulatory function, MnPs should be considered as a safer alternative to other clinical immunosuppressive agents (i.e., rapamycin) for transplantation. Future Directions: Although MnP likely affects only redox-sensitive targets, the mechanism behind global T-cell immunosuppression and the outcome on infection clearance will have to be elucidated. Based on the increased primary engraftment seen with MnP use, protection against primary nonfunction in porcine to human xenotransplants would likely be enhanced. Further, a better understanding of MnP oxidoreductase function may allow for its use in other chronic inflammatory conditions. Antioxid. Redox Signal. 20, 2465-2477. © Copyright 2014, Mary Ann Liebert, Inc. 2014.