The purpose of this review is to show several examples how the brain-to-blood efflux transport system contributes for the cerebral distribution of the hydrophilic drug and endogenous compound. Based on the distributed model analysis, we have clarified that the restricted cerebral distribution of 3'-Azido-3'-deoxythymidine (AZT) and quinolone antibiotics is attributed to the significant brain-to-blood transport activity of the blood-brain barrier, while only limited contribution of the CSF-to-blood transport at the blood-CSF barrier was indicated for the restricted cerebral distribution. These results suggest that the drug distribution in the brain is strictly regulated by the function of the blood-brain barrier transport, but not that of the blood-CSF barrier for the CSF. In other words, the brain-to-blood efflux transport system at the blood-brain barrier is the major target to overcome the problem of the drug targeting to the brain. By using the brain efflux index method and the conditionally immortalized cell line for the brain capillary endothelial cells in mouse and rats, we have clarified several mechanism of the brain-to-blood transport at the blood-brain barrier in rats and mouse as follows; 1) GAT2/BGT-1 is for GABA, 2) ASCT2 is for L-Asp, but not for D-Asp, 3) OAT3 is for homovanillic acid, indoxyl sulfate, 6-mercaptopurine, 6-thioguanine, 4) oatp2 is for dehydroepiandrosterone sulfate. In conclusion, the blood-brain barrier has an important physiological function for supporting and protecting the brain function by withdrawing some neurotransmitters, neuromodulator, metabolites of neurotransmitter and neurosteroid, uremic toxin and hydrophilic xenobiotics in the brain interstitial fluid to the circulating blood. As perspective, quantitative proteomics based pharmacokinetics, i. e., pharmacoproteomics would significantly facilitate the blood-brain barrier in the near future. Recently, we have established a new method to quantify the membrane protein such as transporter, receptor and enzyme by using LC-MS/MS. Now, it is possible to clarify the human blood-brain barrier transporters/receptors/enzymes in a quantitative manner. This new approach will enable us to clarify the interspecies difference, ageing effect, disease effect of the blood-brain barrier, which must be significantly important knowledge for the CNS drug discovery and development.