At some point during their lives, many patients with schizophrenia abuse substances. The co-occurrence of substance use leads to poorer long- and short-term outcomes in schizophrenia and complicates the treatment of both conditions. The primary substances of abuse among schizophrenia patients are alcohol, cannabis, cocaine, and nicotine. This presentation describes the prevalence, outcomes, and basis for this comorbidity. A brief discussion about the neurobiology of schizophrenia explains how schizophrenia may create a biologic predisposition to substance abuse by altering the brain reward system. The efficacy of possible treatments for comorbid schizophrenia and substance abuse are weighed, including typical and atypical antipsychotics and psychosocial interventions, and a list of possible adjunctive agents is provided.