In this manuscript, our recent studies on the transporters on the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the excretion of ligands from the central nervous system (CNS) to the blood are summarized. By comparing the brain entry of quinidine in normal and mdr 1a knock out mice, the predominant role of P-glycoprotein in the brain distribution of this compound was demonstrated. In addition to P-glycoprotein, the presence of transporters responsible for the efflux of organic anions from the brain has been suggested by a pharmacokinetic analysis of the CNS distribution of cefodizime, a third generation cephalosporin antibiotic. This suggestion was confirmed by demonstrating the presence of a specific mechanism for the elimination of p-aminohippuric acid from the brain after microinjection into the cerebral hemisphere. In vitro, the energy-dependent luminal preferential efflux of glutathione-bimane was demonstrated in a monolayer of MBEC4 cells which were derived from mouse brain endothelial cells. Studies with isolated membrane vesicles from MBEC4 cells suggested the presence of a primary active transporter(s) for organic anions, and Western blot analysis indicated the presence of multidrug resistance associated protein (MRP1) and/or its related transporters on MBEC4 cells and freshly isolated rat cerebral endothelial cells. The transcellular transport of 17beta estradiol 17beta-D-glucuronide (E(2)17betaG) across the choroid plexus was also demonstrated by examining the efflux of this compound from CSF after intracerebroventricular administration. The functional significance of organic anion transporting polypeptide (oatp-1) on the brush border membrane of the choroid plexus was demonstrated by comparing the uptake of E(2)17betaG into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in addition, reverse transcription-polymerase chain reaction and Western blot analysis indicated the presence of MRP in the choroid plexus. Together with the direction of transcellular transport, the basolateral localization of MRP on the choroid plexus was suggested. By regulating the activity of these efflux transporters, it is possible to improve the brain entry of certain substrates.