Substance use disorder is the most common psychiatric comorbidity in patients with schizophrenia, revealing prevalence rates of up to 65%. Recommendations of antipsychotic pharmacotherapy in schizophrenia are based on studies excluding patients with this double diagnosis. In this systematic review the available pharmacological studies in this subgroup of patients are summarised and discussed with regard to evidence-based medicine. Most available studies concern small sample sizes, and the level of evidence in those studies was low. Data suggest efficacy for second-generation antipsychotics (SGAs) (aripiprazole, clozapine, olanzapine, quetiapine, and risperidone) superior to orally administered conventional antipsychotics. Treatment with SGAs revealed superior improvement of distinct psychopathological symptoms, similarly to those studies excluding patients with comorbid substance abuse. In some studies reduced craving and increased reduction of substance abuse could be demonstrated. Tricyclic antidepressants (TCAs) added to antipsychotic maintenance therapy showed efficacy in reducing substance abuse and craving, whereas studies with other antidepressive agents (e.g. selective serotonin reuptake inhibitors) are lacking. Administration of the anti-craving agents naltrexone and disulfiram led to a decrease of drug intake in a few studies. Unfortunately no studies are available using acamprosate in patients with schizophrenia and comorbid alcoholism. In conclusion the preferential use of SGAs in patients with schizophrenia and comorbid substance use disorder is suggested, and the early initiation of concomitant treatment with TCAs (depending on current psychopathological status) and anti-craving agents has to be considered.