Substance use disorder (SUD) occurs commonly in patients with schizophrenia and is associated with a poor outcome. Despite this common co-morbid occurrence (and its negative impact on the course of schizophrenia), there have been very few studies assessing pharmacological strategies for optimal treatment of these patients. A number of theories have been advanced to help explain the high rate of substance use disorder in patients with schizophrenia. Our group has suggested that the brain reward circuit dysfunction model, which may incorporate aspects of all of these models, may help direct research aimed at developing new pharmacological treatments for patients with schizophrenia and co-occurring SUD. Although typical antipsychotic medications appear to be of limited value in these patients, emerging, but preliminary, data suggest that the atypical antipsychotics, particularly clozapine, may be particularly helpful. The role of adjunctive medications, such as those medications that have recently been shown to be useful for the treatment of alcoholism, may have a role in the treatment of these patients, although only naltrexone has, thusfar, been carefully tested in these comorbid patients. Further studies are indicated to assess the role of novel pharmacologic treatment strategies for these patients. Ultimately, any medication given to these patients will need to be prescribed within psychosocial treatment programs aimed at assisting these patients in limiting and ultimately ceasing substance use.