1. The pathogenesis of bilirubin encephalopathy is multifactorial, involving the transport of bilirubin or albumin/bilirubin across the blood-brain barrier and delivering bilirubin to target neurons. 2. The relative importance of the blood-brain barrier, unconjugated bilirubin levels, serum binding, and tissue susceptibility in this process is only partially understood. Even at dangerously high serum levels, bilirubin traverses the intact blood-brain barrier slowly, requiring time for encephalopathy to occur, although deposition of bilirubin can be rapid if a surge in plasma unbound bilirubin is produced by administering a drug which competes with bilirubin for binding to albumin. 3. There may be maturational changes in permeability both in the fetus and postnatally which protect the brain from bilirubin. 4. Disruption or partial disruption of the blood-brain barrier by disease or hypoxic ischemic injury will facilitate transport of bilirubin/albumin into brain, but the relative affinities of albumin and target neurons will determine whether the tissue bilirubin load is sufficient for toxicity to occur.