Growing evidence points to synaptic pathology as a core component of the pathophysiology of schizophrenia (SZ). Significant reductions of dendritic spine density and altered expression of their structural and molecular components have been reported in several brain regions, suggesting a deficit of synaptic plasticity. Regulation of synaptic plasticity is a complex process, one that requires not only interactions between pre- and post-synaptic terminals, but also glial cells and the extracellular matrix (ECM). Together, these elements are referred to as the ‘tetrapartite synapse’, an emerging concept supported by accumulating evidence for a role of glial cells and the extracellular matrix in regulating structural and functional aspects of synaptic plasticity. In particular, chondroitin sulfate proteoglycans (CSPGs), one of the main components of the ECM, have been shown to be synthesized predominantly by glial cells, to form organized perisynaptic aggregates known as perineuronal nets (PNNs), and to modulate synaptic signaling and plasticity during postnatal development and adulthood. Notably, recent findings from our group and others have shown marked CSPG abnormalities in several brain regions of people with SZ. These abnormalities were found to affect specialized ECM structures, including PNNs, as well as glial cells expressing the corresponding CSPGs. The purpose of this review is to bring forth the hypothesis that synaptic pathology in SZ arises from a disruption of the interactions between elements of the tetrapartite synapse.