Objective: To study the association of family and social risk factors with psychopathology in a longitudinal study of adolescents. Method: From 1986 to 1988, 3,419 seventh through ninth graders were screened with the Center for Epidemiologic Studies Depression Scale. The top decile scorers and a random sample of the remainder were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (n = 581). Follow-up interviews were completed 6 years later (mean age = 18.65; n = 490). Baseline variables are associated with baseline and follow-up diagnoses. Diagnoses are grouped by affective, disruptive, and anxiety disorders. Results: The frequency of psychiatric diagnosis decreased from 19.9% (baseline) to 5.7% (follow-up). In multivariable logistic regression analyses controlling for race, gender, and socioeconomic status, baseline undesirable life events and low family cohesion are associated with any disorder and affective disorder at baseline. Not living with both biological parents at baseline increases the odds ratio (OR) for affective disorder at baseline (OR 3.45; 95% confidence interval [CI] = 1.68-7.08) and follow-up (OR 4.40; CI = 1.26-15.40). At baseline and follow-up, anxiety and affective disorders are associated with being white and anxiety disorder with being female. Conclusions: Family structure and cohesion and stressful life events are associated with affective disorders in adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 2005;44(2):121-129. Key Words: risk factors, psychopathology, adolescents.