The glutamate system includes presynaptic glutamatergic terminals, complex post-synaptic densities found on diverse types of neurons expressing glutamate receptors, as well as glutamate transporters and enzymes that facilitate the glutamate/glutamine cycle. Abnormalities of this system have been implicated in schizophrenia based on an accumulating body of evidence from postmortem, imaging, and preclinical studies. However, recent work has suggested that astrocytes may have more than a bystander role in the synchronization of neuronal responses in the brain. Converging evidence suggests that extrasynaptic glutamate microdomains are formed by astrocytes and may facilitate neuroplasticity via the modulation of extra-synaptic glutamate receptors on neuronal membranes within these domains. In this article the authors propose that the composition and localization of protein complexes in glutamate microdomains is abnormal in schizophrenia, leading to pathological neuroplastic changes in the structure and function of glutamate circuits in this illness.