The rate of substance-use disorders in patients with mental illnesses within the psychotic spectrum, such as schizophrenia, schizoaffective disorder, and bipolar disorder, is higher than the rate observed in the general population and is associated with significant morbidity and mortality. Although there are currently 3 medications approved by the Food and Drug Administration for the treatment of alcohol dependence, no medications have been approved for the specific treatment of dually diagnosed patients. A small but growing body of literature supports the use of 2 of these medications, disulfiram and naltrexone, in dually diagnosed individuals. This article outlines a review of the literature about the use of disulfiram and naltrexone for alcoholism and in patients with comorbid mental illness. In addition, results are presented of a 12-week randomized clinical trial of disulfiram and naltrexone alone and in combination for individuals with Axis I disorders and alcohol dependence who were also receiving intensive psychosocial treatment. Individuals with a psychotic spectrum disorder, including schizophrenia, schizoaffective disorder, and bipolar disorder, had worse alcohol outcomes than those without a psychotic spectrum disorder. Individuals with a psychotic spectrum disorder had better alcohol-use outcomes on an active medication compared with placebo, but there was no clear advantage of disulfiram or naltrexone or of the combination. Retention rates and medication compliance in the study were high and exceeded 80%. Pharmacotherapeutic strategies should take into account the advantages and disadvantages of each medication. Future directions of pharmacotherapeutic options are also discussed.