The conventional model of glucose transport into brain assumes unregulated symmetrical passive transport across the blood brain barrier (BBB) defined by global Michaelis-Menten parameters (Kt = 5-10mM; Vmax 1μmol/g/min). Steady-state [glucose] = 1mM in the brain extracellular fluid (ecf) is maintained by removal of glucose by brain metabolism (Gruetter et al. 1998). The model predicts that glucose flow between blood and ecf is 70% maximal. However, local stimulation can raise regional brain glucose metabolism by at least 100% above basal rates and dialysis studies show only small decreases in ecf [glucose] on stimulation of brain metabolism (McNay, McCarty & Gold, 2001). These findings indicate that glucose transport across the BBB is seemingly more responsive to brain metabolism than the model permits. Hexokinase co-localizes with glucose transporters (GLUTs) at the luminal and abluminal surfaces of the BBB, including endothelial and astroglial layers. GLUTs and hexokinase are more abundant on the abluminal surface. Hexokinase retards glucose exit from glia to ecf (McAllister et al., 2001). Glucose-6-phosphatase (G6P) is also present within glia, (Bell et al., 1993) thereby permitting glucose regeneration from G6P and its accumulation within the cytosol. Cytosolic glucose accumulation in glia and endothelia retards net uptake across the endothelial luminal membrane. Glucose exit across the glial abluminal membrane is reduced by conversion to G6P via membrane-bound hexokinase. Reduction in ecf [glucose] induced by brain metabolism increases the glucose concentration gradients across both luminal and abluminal membranes, thereby raising net flux into brain. Modelling these relationships with a fast simulation program, (Berkeley Madonna, www.berkeleymadonna.com), shows that regulation of BBB glucose flow depends on the extent of its accumulation within the cytosol. Reversible phosphorylation of 2-deoxy 2-fluoro-D-glucose (2FDG) in glia leads to more rapid and greater accumulation in brain than the non-metabolised, 3-O-methyl-glucoside (3-OMG). When matched with PET scans of human brain, the model simulations are consistent with these predictions in both euglycaemic and hypoglycaemia conditions.