Although rare, extreme neonatal hyperbilirubinemia and its dreaded complication, kernicterus, continue to occur. Hyperbilirubinemia develops when bilirubin production exceeds the body's capacity to excrete it, primarily by conjugation. Genetic, environmental, and racial factors affecting the equilibrium between these processes are discussed. Adjuncts to the interpretation of the serum total bilirubin concentration are suggested. Prevention and management of severe hyperbilirubinemia should be based on American Academy of Pediatrics guidelines, with individualization including earlier institution of treatment and delayed discharge from the hospital for neonates with risk factors for kernicterus.