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The N-Methyl-D-aspartate–type glutamate receptor (NMDAR) plays a key role in several important processes involving the nervous system, including brain development, synaptic plasticity, and learning. Unlike other neurotransmitter receptors, which are activated by individual neurotransmitters, activation of NMDARs requires the binding of a coagonist (D-serine or glycine) in addition to glutamate. Although previously considered an "unnatural" amino acid, D-serine is a key regulator of NMDAR activity and may be the main physiological ligand at the coagonist site. D-Serine is synthesized in the mammalian brain and is enriched in astrocytes, a class of glial cells that ensheath synapses in the brain. Astrocytes physiologically affect NMDAR neurotransmission by releasing D-serine, suggesting that D-serine acts as a gliotransmitter. However, recent findings indicate that D-serine signaling does not depend solely on glia, because D-serine and its biosynthetic enzyme are also present in substantial amounts in neurons. Here, we discuss these new findings, which begin to shed light on the relative roles of glia and neurons in D-serine signaling.