P-glycoprotein (Pgp), an ATP-dependent plasma membrane efflux pump, is expressed in abundance on the luminal aspect of brain capillary endothelial cells and astrocytes of the blood-brain barrier where it limits the passage of a variety of lipophilic substrates into the central nervous system. This review summarizes current evidence characterizing (1) unconjugated bilirubin as a potential substrate for Pgp and (2) the ontogeny of Pgp expression at the blood-brain barrier and apical brush border epithelium of the gastrointestinal tract, findings that may provide insights regarding the disposition of bilirubin in immature subjects.