This study examines disparities in co-occurring mental health and substance use problems by race/ethnicity to inform the development of culturally appropriate treatment approaches. Using pooled clinical data collected with the Global Assessment of Individual Needs, we identified racial/ethnic and other factors associated with co-occurring internalizing problems, externalizing problems, and the combination thereof in adolescents in federally funded treatment facilities. Results show that after controlling for demographic and socioenvironmental factors, African Americans, Hispanics, and mixed-race adolescents were more likely than Whites to have co-occurring internalizing problems. African Americans and Native Americans were less likely than Whites to have externalizing problems and to have combined internalizing and externalizing problems. Presence of co-occurring problems was also associated with victimization, homelessness, and family substance abuse. These results indicate that co-occurring mental health problems vary by race/ethnicity, and therefore, refined approaches are needed for culturally appropriate care of patients.