Substance abuse is a frequent comorbid condition with other psychiatric disorders including schizophrenia and depression. These disorders may share a common substrate at the neurotransmitter or neurocircuit level. One candidate is hypofunction of the glutamate system. Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptors may hypofunction in schizophrenia. Thus, NMDA receptor antagonists are schizophrenogenic; postmortem and imaging results point to reduced NMDA receptor function in schizophrenic brains; a number of genes that have been linked to schizophrenia code for proteins that influence NMDA function; and there is preliminary evidence that pro-NMDA drugs may be therapeutic in the treatment of schizophrenia. One of the most effective therapeutics for the treatment of substance abuse in schizophrenic people is clozapine, and clozapine may act at the glycine modulatory site to enhance NMDA receptor function. This preliminary line of evidence may link schizophrenia and drug abuse to a common neurochemical base, subnormal NMDA receptor function. People with schizophrenia and drug abusers similarly show deficits in tasks known to be sensitive to ventromedial prefrontal cortical damage, and both groups show decreased activation in the ventral striatum during reward anticipation in functional magnetic resonance imaging studies. These observations implicate common prefrontal cortical-striatal circuits and their modulation by hippocampal projections in schizophrenia and substance abuse. Withdrawal from substance abuse and depression both have been linked to changes in the function of several neurotransmitters including serotonin, dopamine and glutamate. These findings suggest possible common substrates and novel therapeutic approaches. Further studies are needed to fully characterize the neurocircuits and transmitters involved in various psychiatric disorders and their possible common elements in comorbid drug abuse.