Dysfunctional glial cells play a pre-eminent role in schizophrenia pathophysiology. Post-mortem studies have provided evidence for significantly decreased glial cell numbers in different brain regions of individuals with schizophrenia. Reduced glial cell numbers are most pronounced in oligodendroglia, but reduced astrocyte cell densities have also been reported. This review highlights that oligo- and astroglial deficits are a key histopathological feature in schizophrenia, distinct from typical changes seen in neurodegenerative disorders. Significant deficits of oligodendrocytes in schizophrenia may arise in two ways: (i) demise of mature functionally compromised oligodendrocytes
and (ii) lack of mature oligodendrocytes due to failed maturation of progenitor cells. We also analyse in detail the controversy regarding deficits of astrocytes. Regardless of their origin, glial cell deficits have several pathophysiological consequences. Among these, myelination deficits due to a reduced number of oligodendrocytes may be the most important factor, resulting in the disconnectivity between neurons and different brain regions observed in schizophrenia. When glial cells die, it appears to be through degeneration, a process which is basically reversible. Thus, therapeutic interventions that (i) help rescue glial cells (ii) or improve their maturation might be a viable option. Since antipsychotic treatment alone does not seem to prevent glial cell loss or maturation deficits, there is intense search for new therapeutic options. Current proposals range from the application of antidepressants and other chemical agents as well as physical exercise to engrafting healthy glial cells into brains of schizophrenia patients.