Epidemiologic studies indicate that co-occurring substance use disorders and psychiatric disorders are frequently found in clinical practice. From a neurobiologic perspective, what do these two seemingly different groups of disorders have in common? Currently, several hypotheses are postulated to explain the high rates of comorbidity. Chronic alcohol and drug use may lead to neuroadaptation in the biologic systems mediating psychiatric disorders. Conversely, co-occurring psychiatric and substance use disorders (SUDs) may represent phenotypic expressions of common premorbid neurobiologic abnormalities. Similar alterations in the dopamine-mediated reward system and various neurotransmitter systems including glutamate, γ-aminobutyric acid, and serotonin are found in both SUDs and numerous psychiatric disorders. Stress and chronic distress with the resultant activation of the hypothalamic-pituitary-adrenal axis and stress system has also been implicated in the pathophysiology of both psychiatric disorders and SUDs. Better understanding the commonalities between the two groups of disorders should lead to more efficacious treatments and targeted prevention strategies.