Impaired cognitive functioning, including deficits in working memory, is considered to be a core and disabling feature of schizophrenia that is difficult to treat. Deficits in working memory in schizophrenia are attributable, at least in part, to specific pathological alterations in the neuronal circuitry of the dorsolateral prefrontal cortex that involve, but are not restricted to, disturbances in glutamate, GABA, and dopamine neurotransmission. Cannabis use provides an example of an environmental exposure that may have a deleterious impact on these neurotransmitter systems and thereby contribute to worsening of cognitive functioning in schizophrenia. Increasing knowledge of the nature of the molecular alterations in these cortical circuits may lead to the development of new pathophysiologically informed treatment options for cognitive deficits in schizophrenia.