D-Serine is a brain-enriched D-amino acid that works as a transmitter-like molecule by physiologically activating NMDA receptors. Synthesis of D-serine is carried out by serine racemase (SR), a pyridoxal 5'-phosphate-dependent enzyme. In addition to carry out racemization, SR alpha,beta-eliminates water from L- or D-serine, generating pyruvate and NH(4)(+). Here I review the main mechanisms regulating SR activity and D-serine dynamics in the brain. I propose a role for SR in a novel form of astrocyte-neuron communication-the "serine shuttle", whereby astrocytes synthesize and export L-serine required for the synthesis of D-serine by the predominantly neuronal SR. D-Serine synthesized and released by neurons can be further taken up by astrocytes for storage and activity-dependent release. I discuss how SR alpha,beta-elimination with D-serine itself may limit the achievable intracellular D-serine concentration, providing a mechanistic rationale on why neurons do not store as much D-serine as astrocytes. The higher content of D-serine in astrocytes appears to be related to increased D-serine stability, for their low SR expression will prevent substantial D-serine metabolism via alpha,beta-elimination. SR and the serine shuttle pathway are therapeutic targets in neurodegenerative diseases in which NMDA receptor dysfunction plays pathological roles. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology. (C) 2011 Elsevier B.V. All rights reserved,