The role played by efflux transport systems across the blood-brain barrier (BBB) in the disposition of xenobiotics in the brain is described. Several drugs and organic anions are transported across the BBB via P-glycoprotein and other carrier-mediated efflux transport systems. Studies using in vitro cultured brain capillary endothelial cells, kinetic analysis, and mdr1a gene knock-out mice have shown that P-glycoprotein, located on the BBB, restricts the entry of vincristine and quinidine to the brain. Brain microdialysis studies have demonstrated that the brain interstitial fluid (ISF) concentrations of quinolone antibiotics are significantly lower than their corresponding unbound serum concentrations. A distributed model analysis supports the finding that efflux transport systems on the BBB restrict distribution of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), and quinolone antibiotics. A brain efflux index (BEI) method has been developed to provide direct evidence of an efflux transport system for carrying substrates from the cerebrum to the circulating blood across the BBB. The BEI method revealed the existence of carrier-mediated efflux organic anion transport systems for compounds such as p-aminohippuric acid, AZT, DDI, taurocholic acid, BQ-123, and estron sulfate. Moreover, cerebral neurotransmitters such as gamma-aminobutyric acid, L-glutamic acid, and L-aspartic acid are transported from brain to the circulating blood in the intact form via a carrier-mediated efflux transport system. The BBB not only restricts nonspecific permeation from the circulating blood to the brain, but also functions as an active efflux transport system for xenobiotics. Accordingly, the BBB plays a very important role by pumping xenobiotics and some endogenous compounds out of the brain, acting as a central nervous system (CNS)-specific detoxifying system supporting and maintaining normal cerebral function.