The rate of comorbid substance use disorder in patients with schizophrenia is 3 times higher than that in the general population. Men with schizophrenia appear to be particularly vulnerable to substance use disorders. Substances commonly abused in patients with schizophrenia include alcohol, cannabis, and cocaine. Although the basis of comorbidity is unclear, a number of theories have been proposed, including the possibility of a deficiency in the dopamine-mediated mesocorticolimbic brain reward circuit. Data suggest that substance abuse may complicate and worsen the course of schizophrenia. Early intervention with appropriate pharmacotherapy may prove beneficial and potentially improve the long-term course of the disorder. Conventional antipsychotics have not been overly useful in this patient population, but some atypical antipsychotics have been shown to reduce the use of alcohol, cannabis, cocaine, and tobacco in patients with schizophrenia. Further research is required, but early evidence suggests that at least some atypical antipsychotics may prove to be therapeutically effective in the treatment of patients with schizophrenia and comorbid substance use disorder.