Adolescence is a high-risk period for development of both depressive and substance use disorders. These two disorders frequently co-occur in adolescents and are associated with significant morbidity and mortality. Given the added economic and psychosocial burden associated with the comorbid condition, identification of risk factors associated with their co-occurrence is of great public health importance. Research with adult animals and humans has indicated several common neurobiological systems that link depressive and addictive disorders. Given the ongoing maturation of these systems throughout adolescence and early adult life, it is not clear how these neurobiological processes influence development and progression of both disorders. A better understanding of the pathophysiological mechanisms leading to the onset and course of these disorders during adolescence will be helpful in developing more effective preventive and treatment strategies, and thereby allow these youth to reach their full potential as adults.