BACKGROUND: Mood disorders, especially bipolar disorder (BD), frequently are associated with substance use disorders (SUDs). There are well-designed trials for the treatment of SUDs in the absence of a comorbid condition. However, one cannot generalize these study results to individuals with comorbid mood disorders, because therapeutic efficacy and/or safety and tolerability profiles may differ with the presence of the comorbid disorder. Therefore, a review of the available evidence is needed to provide guidance to clinicians facing the challenges of treating patients with comorbid mood disorders and SUDs. METHODS: We reviewed the literature published between January 1966 and November 2010 by using the following search strategies on PubMed. Search terms were bipolar disorder or depressive disorder, major (to exclude depression, postpartum; dysthymic disorder; cyclothymic disorder; and seasonal affective disorder) cross-referenced with alcohol or drug or substance and abuse or dependence or disorder. When possible, a level of evidence was determined for each treatment using the framework of previous Canadian Network for Mood and Anxiety Treatments recommendations. The lack of evidence-based literature limited the authors' ability to generate treatment recommendations that were strictly evidence based, and as such, recommendations were often based on the authors' opinion. RESULTS: Even though a large number of treatments were investigated for alcohol use disorder (AUD), none have been sufficiently studied to justify the attribution of level 1 evidence in comorbid AUD with major depressive disorder (MDD) or BD. The available data allows us to generate first-choice recommendations for AUD comorbid with MDD and only third-choice recommendations for cocaine, heroin, and opiate SUD comorbid with MOD. No recommendations were possible for cannabis, amphet-amines, methamphetamines, or polysubstance SUD comorbid with MDD. First-choice recommendations were possible for alcohol, cannabis, and cocaine SUD comorbid with BD and only second-choice recommendations for heroin, amphetamine, methamphetamine, and polysubstance SUD comorbid with BD. No recommendations were possible for opiate SUD comorbid with BD. Finally, psychotherapies certainly are considered an essential component of the overall treatment of SUDs comorbid with mood disorders. However, further well-designed studies are needed in order to properly assess their potential role in specific SUDs comorbid with a mood disorder. CONCLUSIONS: Although certain treatments show promise in the management of mood disorders comorbid with SUDs, additional well-designed studies are needed to properly assess their potential role in specific SUDs comorbid with a mood disorder.