PURPOSE OF REVIEW: The presentation of major depressive disorder is often complicated by the co-occurrence of substance use disorders, such as alcohol and illicit drug abuse or dependence. The article reviews the recent systematic research on the distinguishing baseline characteristics including demographic characteristics and the influence of family history, and clinical features such as depressive symptomatology and suicidal ideation, and the outcome of treatment for depression in patients with comorbid major depressive disorder and substance use disorders. The review also addresses the possible explanations cited in the literature as to why these two disorders tend to co-occur and the implications of the comorbidity of these illnesses on treatment. RECENT FINDINGS: Nearly one-third of patients with major depressive disorder also have substance use disorders, and the comorbidity yields higher risk of suicide and greater social and personal impairment as well as other psychiatric conditions. Although the treatment of comorbid major depressive disorder and substance use disorders with medication is likely effective, the differential treatment effects based on substance use disorder comorbidity have been understudied. SUMMARY: Emerging results of recent studies comparing the outcome of major depressive disorder patients with comorbid major depressive disorder and substance use disorders suggest that there are fewer differential effects based on comorbidity than previously anticipated by older assumptions from smaller, less methodologically rigorous studies. © 2008 Lippincott Williams & Wilkins, Inc.