This chapter begins with an overview of substance use disorder (SUD) in adolescents followed by a review of the neurobiologic mechanisms of SUD and ends with some practical guidelines for the management of young people with SUD and comorbid psychiatric disorders. SUDs are characterized by the constellation of symptoms and maladaptive behavioral changes associated with the regular use of psychoactive substances. The chapter discusses addiction referring to a chronic, compulsive pattern of substance use leading to tolerance, withdrawal symptoms, and/or other physiologic changes. Treatment of withdrawal states can typically be achieved by replacing the abused drug with a drug of similar pharmacologic actions. Maintenance treatment with agonists is designed to support many patients with chronic relapsing opioid dependence. The goals of pharmacologic treatments include reduction in craving/subjective effects of abused substances, prevention of relapse, and treatment of comorbid psychiatric disorders.