Bilirubin, a pigment associated with jaundice, has long been considered to lack a clear physiological role. However, this study reveals that bilirubin is a major physiologic antioxidant and cytoprotectant. It is produced by the enzymatic reduction of biliverdin by biliverdin reductase (BVR), which is then recycled back to bilirubin through a redox cycle. This cycle allows bilirubin to act as a potent antioxidant, protecting cells from oxidative stress. The study shows that depletion of bilirubin by RNA interference significantly increases reactive oxygen species (ROS) levels and causes cell death, while depletion of glutathione has a lesser effect. The redox cycle of BVR provides a mechanism for bilirubin to amplify its antioxidant effects, enabling it to protect cells from extremely high concentrations of hydrogen peroxide. The study also demonstrates that bilirubin is a physiologic antioxidant neuroprotectant, as mice with HO2 deletion are more susceptible to stroke and seizure-induced damage. The findings suggest that the BVR cycle is a principal physiologic function of bilirubin, providing cytoprotection against oxidative stress. The study also highlights the clinical relevance of bilirubin, as high levels are associated with reduced risks of cardiovascular disease and cancer mortality. The results indicate that bilirubin's physiological role in mammals is primarily cytoprotective, and its production may have evolved to serve this function.Bilirubin, a pigment associated with jaundice, has long been considered to lack a clear physiological role. However, this study reveals that bilirubin is a major physiologic antioxidant and cytoprotectant. It is produced by the enzymatic reduction of biliverdin by biliverdin reductase (BVR), which is then recycled back to bilirubin through a redox cycle. This cycle allows bilirubin to act as a potent antioxidant, protecting cells from oxidative stress. The study shows that depletion of bilirubin by RNA interference significantly increases reactive oxygen species (ROS) levels and causes cell death, while depletion of glutathione has a lesser effect. The redox cycle of BVR provides a mechanism for bilirubin to amplify its antioxidant effects, enabling it to protect cells from extremely high concentrations of hydrogen peroxide. The study also demonstrates that bilirubin is a physiologic antioxidant neuroprotectant, as mice with HO2 deletion are more susceptible to stroke and seizure-induced damage. The findings suggest that the BVR cycle is a principal physiologic function of bilirubin, providing cytoprotection against oxidative stress. The study also highlights the clinical relevance of bilirubin, as high levels are associated with reduced risks of cardiovascular disease and cancer mortality. The results indicate that bilirubin's physiological role in mammals is primarily cytoprotective, and its production may have evolved to serve this function.