Severe unconjugated hyperbilirubinemia, seen mainly in neonates, may cause kernicterus and death. Conventional treatment for severe unconjugated hyperbilirubinemia consists of phototherapy and exchange transfusion. Phototherapy, however, has several known disadvantages while exchange transfusion is associated with a significant morbidity, and even mortality. These harmful effects indicate the need to develop alternative pharmacological treatment strategies for unconjugated hyperbilirubinemia. Generally, these strategies aim to decrease the plasma concentration of unconjugated bilirubin (UCB) by inhibiting production, stimulating hepatic clearance, or interrupting the enterohepatic circulation of the pigment. To be considered for routine clinical use, an alternative treatment strategy should be less invasive and at least as effective and safe as phototherapy. Several pharmacological therapies such as metalloporhyrins, clofibrate, bile salts, laxatives and bilirubin oxidase may meet these criteria in the future, but none of them has yet been evaluated sufficiently to allow routine application. This review aims to discuss the state of the art and future perspectives in pharmacological treatment of neonatal jaundice.