Bilirubin, an old tetrapyrrolic compound that had occurred on Earth early on, is the final product of the catabolic heme pathway in the intravascular bed. Data from recent decades revealed its enormous bioactivity in a human body, including antioxidant, anti-inflammatory, immunosuppressive, antiproliferative, and even cell signaling activities that translate into beneficial effects of mildly elevated serum bilirubin concentrations resulting in prevention or amelioration of progression of many diseases of civilization. Furthermore, recent advances in bilirubin research have changed our understanding of bilirubin metabolism in the neonatal period, with discoveries of bilirubin reductase of bacterial origin in the intestinal lumen with direct pathophysiological and clinical implications. Similarly, our knowledge of the pathophysiology of neonatal jaundice phototherapy has improved substantially, although we are still at the beginning of the path to understand all the pathophysiological aspects and reveal related clinical implications. BULLET POINTS: Recent advances in our understanding of bilirubin metabolism with clear clinical implications, as well as other, so far putative, translational impacts. Demonstration of the beneficial biological potential of bilirubin, its evolutionary and ontogenetic functions, its possible role in chronobiology, and its correlation with increased fitness in elite athletes (a sort of gain of function). Discussion on the protective role of physiological neonatal jaundice. Inspiration for further basic and clinical research in specific fields of bilirubin metabolism.

4th Department of Internal Medicine and Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

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