Substance dependence has serious negative consequences upon society such as increased health care costs, loss of productivity, and rising crime rates. Although there is some preliminary evidence that atypical antipsychotic agents may be effective in treating substance dependence, results have been mixed, with some studies demonstrating positive and others negative or no effect. The present study was aimed at determining whether this disparity originates from that reviewers separately discussed trials in patients with (DD) and without (SD) comorbid psychosis. Using electronic databases, we screened the relevant literature, leaving only studies that used a randomized, double-blind, placebo-controlled or case-control design that had a duration of 4 weeks or longer. A total of 43 studies were identified; of these, 23 fell into the category of DD and 20 into the category of SD. Studies in the DD category suggest that atypical antipsychotic agents, especially clozapine, may decrease substance use in individuals with alcohol and drug (mostly cannabis) use disorders. Studies in the SD category suggest that atypical antipsychotic agents may be beneficial for the treatment of alcohol dependence, at least in some subpopulations of alcoholics. They also suggest that these agents are not effective at treating stimulant dependence and may aggravate the condition in some cases.