Antidepressants are commonly used in substance abusers due to the potential effect on some underlying mechanisms involved in drug use disorders and to treat comorbid depression. A systematic review of the literature of the efficacy of antidepressant drugs in subjects with drug abuse disorders, including alcohol, cocaine, nicotine and opioid, with and without comorbid depression was performed. Only randomised, double-blind, controlled trials have been evaluated. A meta-analysis was done with the included studies that used common evaluation procedures in alcohol, cocaine and opioid dependence. Based on the present review some recommendations may be proposed. The prescription of antidepressants for drug abuse seems only clear for nicotine dependence with or without previous comorbid depression (bupropion and nortryptiline). In alcohol dependence without comorbid depression, the use of any antidepressant seems not justified, while in cocaine dependence has to be clarified. The use of antidepressants in alcohol, cocaine or opioid dependence with comorbid depression needs more studies in well-defined samples, adequate doses and duration of treatment to be really conclusive. Interestingly, SSRIs do not seem to offer significant advantages compared with tricyclic drugs in substance abuse disorders. Differences both related to individual characteristics and specific antidepressant drugs need to be clarified in future studies.