Research on the structure of adolescent psychopathology can provide information on broad factors that underlie different forms of maladjustment in youths. Multiple studies from the literature on adult populations suggest that 2 factors, Internalizing and Externalizing, meaningfully comprise the factor structure of adult psychopathology (e.g., Krueger, 1999) and presumably represent broad vulnerability for co-occurring disorders. Though this research was partially inspired by early work with children and adolescents (e.g., Achenbach & Edelbrock, 1984), the role of substance use in these models of youth psychopathology has not been fully explored. Toward this goal, we recruited 223 youths (10-17 years of age, M = 14.2) from mental health agencies and the community. We found evidence for a 3-factor model of youth psychopathology, including Internalizing (depression, generalized anxiety), Externalizing (conduct disorder, attention deficit, oppositional defiant disorder), and Substance Use (alcohol and cannabis). The 3-factor model showed the best fit to the data relative to other factor models tested, including across subsamples of adolescents who differed on level of psychopathology (treatment vs. community samples). Implications for the structure of adolescent psychopathology, including important developmental considerations, are discussed. (Contains 1 figure, 4 tables and 4 footnotes.)