NMDA receptors (NMDARs) are key glutamatergic receptors in the CNS. Their permeability to Ca2+ and their voltage-dependent Mg2+ block make them essential for synaptic transmission, synaptic plasticity, rhythmogenesis, gene expression and excitotoxicity. One very peculiar property is that their activation requires the binding of both glutamate and a co-agonist like glycine or D-serine. There is a growing body of evidence indicating that D-serine, rather than glycine as originally thought, is the endogenous ligand for NMDARs in many brain structures. D-serine is synthesized mainly in glial cells and it is released upon activation of glutamate receptors. Its concentration in the synaptic cleft controls the number of NMDAR available for activation by glutamate. Consequently, the glial environment of neurons has a critical impact on the direction and magnitude of NMDAR-dependent synaptic plasticity.