Degradation of heme involves its conversion to biliverdin by heme oxygenase followed by reduction of biliverdin to bilirubin by biliverdin reductase. There is ample evidence for the pleiotropic functions of biliverdin reductase in cell signaling and regulation of gene expression. This enzyme plays a major role in glucose uptake and the stress response. Bilirubin has been shown to behave as a "double-edged sword". It can exert either cytotoxic or cytoprotective effects, depending on the blood and/or tissue concentration of its free fraction, the nature of the target cell or tissue, and the cellular redox state. Its antioxidant effect is the basis for the proposed cardioprotective effect of relatively low blood concentrations of bilirubin in humans with moderate hyperbilirubinemia. This Special Topic forum is intended to serve as a platform for updating information and presenting advances in basic and clinical research in the above and related subjects.