Glutamate concentrations in plasma are 50-100 micromol/L; in whole brain, they are 10,000-12,000 micromol/L but only 0.5-2 micromol/L in extracellular fluids (ECFs). The low ECF concentrations, which are essential for optimal brain function, are maintained by neurons, astrocytes, and the blood-brain barrier (BBB). Cerebral capillary endothelial cells form the BBB that surrounds the entire central nervous system. Tight junctions connect endothelial cells and separate the BBB into luminal and abluminal domains. Molecules entering or leaving the brain thus must pass 2 membranes, and each membrane has distinct properties. Facilitative carriers exist only in luminal membranes, and Na(+)-dependent glutamate cotransporters (excitatory amino acid transporters; EAATs) exist exclusively in abluminal membranes. The EAATs are secondary transporters that couple the Na(+) gradient between the ECF and the endothelial cell to move glutamate against the existing electrochemical gradient. Thus, the EAATs in the abluminal membrane shift glutamate from the ECF to the endothelial cell where glutamate is free to diffuse into blood on facilitative carriers. This organization does not allow net glutamate entry to the brain; rather, it promotes the removal of glutamate and the maintenance of low glutamate concentrations in the ECF. This explains studies that show that the BBB is impermeable to glutamate, even at high concentrations, except in a few small areas that have fenestrated capillaries (circumventricular organs). Recently, the question of whether the BBB becomes permeable in diabetes has arisen. This issue was tested in rats with diet-induced obesity and insulin resistance or with streptozotocin-induced diabetes. Neither condition produced any detectable effect on BBB glutamate transport.