In this paper, we argue that the research base for understanding comorbidity between substance use and other mental disorders needs to be broadened. We specifically advocate for: 1) more prospective epidemiological studies of relationships between alcohol and other drug use disorders and anxiety and mood disorders; 2) greater use of twin study designs to disentangle shared genetic and environmental contributions to comorbidity; 3) prospective neuroimaging studies of the effects of early and sustained alcohol and drug use on the developing adolescent brain; 4) a greater focus on the effects on comorbidity of primary and secondary prevention interventions for substance use, anxiety, affective and conduct disorders among children and adolescents; and 5) better evaluations of the impact of treatment upon persons with comorbid substance use and other mental disorders.