Hyperbilirubinemia is probably the most frequently diagnosed and treated condition in the human newborn. Treatment is aimed at preventing the entry of bilirubin into the brain because of the risk of permanent neurologic damage. The mode by which bilirubin enters the brain, its metabolic fate after entry, and the sites of toxic action are unknown. Using osmotic stress, the blood-brain barrier was opened in rats, permitting entry of bilirubin. However, in this acute model, the bilirubin was rapidly cleared, with a half-time of l.6 hours. To provide chronic exposure, especially in newborn animals, we are now studying two inbred strains of rats which lack glucuronyl transferase.