Although glutamate is usually thought of as the major excitatory neurotransmitter in brain, it is important to note that glutamate has many other fates in brain, including oxidation for energy, incorporation into proteins, and formation of glutamine, γ-aminobutyric acid (GABA), and glutathione. The compartmentation of glutamate in brain cells is complex and modulated by the presence and concentration of glutamate per se as well as by other metabolites. Both astrocytes and neurons distinguish between exogenous glutamate and glutamate formed endogenously from glutamine via glutaminase. There is evidence of multiple subcellular compartments of glutamate within both neurons and astrocytes, and the carbon skeleton of glutamate can be derived from other amino acids and many energy substrates including glucose, lactate, and 3-hydroxybutyrate. Both astrocytes and neurons utilize glutamate, albeit for cell-specific metabolic fates. Glutamate is readily formed in neurons from glutamine synthesized in astrocytes, released into the extracellular space, and taken up by neurons. However, the glutamate-glutamine cycle is not a stoichiometric cycle but rather an open pathway that interfaces with many other metabolic pathways to varying extents depending on cellular requirements and priorities. © 2007 Wiley-Liss, Inc.