Substance use disorders are common in youth, and co-occurring psychiatric disorders are present in the majority of cases. This article reviews clinical considerations unique to the population, including intricacies of assessment and special treatment considerations. Several psychotherapeutic intervention models are discussed, including cognitive-behavioral therapy, dialectic behavior therapy, motivational enhancement therapy/motivational interviewing, family behavior therapy, multidimensional family therapy, and multisystemic therapy. Research on psychopharmacologic treatment is limited, and primarily focuses on mood disorders and attention deficit/hyperactivity disorder. To maximize outcome, recommendations based on practice parameters promote integration of treatment modalities versus serial or concurrent treatment of co-occurring substance use and psychiatric disorders.