Mood disorders, including depression and bipolar disorders, are the most common psychiatric comorbidities among patients with substance use disorders. Treating patients’ co-occurring mood disorders may reduce their substance craving and taking and enhance their overall outcomes. A methodical, staged screening and assessment can ease the diagnostic challenge of distinguishing symptoms of affective disorders from manifestations of substance intoxication and withdrawal. Treatment should maximize the use of psychotherapeutic interventions and give first consideration to medications proven effective in the context of co-occurring substance abuse. Expanded communication and collaboration between substance abuse and mental health providers is crucial to improving outcomes for patients with these complex, difficult co-occurring disorders.