Youth homelessness is a growing problem in the United States. The experience of homelessness appears to have numerous adverse consequences, including psychiatric and substance use disorders. This study compared the frequencies of psychiatric disorders, including substance use, between homeless youth (18–24 years-old) in San Francisco (N = 31) and Chicago (N = 56). Subjects were administered the Mini International Neuropsychiatric Interview (M.I.N.I.) to assess DSM-IV-TR diagnoses and substance use disorders. Eighty-seven percent of the San Francisco youth, and 81% of the Chicago youth met criteria for at least one M.I.N.I. psychiatric diagnosis. Nearly two-thirds of the youth in both samples met criteria for a mood disorder. Approximately one-third met criteria for an anxiety disorder. Thirty-two percent of the San Francisco sample and 18% of the Chicago met criteria for Antisocial Personality Disorder. Approximately 84% of the San Francisco youth and 48% of the Chicago youth met criteria for a substance-related disorder, and more substances were used by San Francisco youth. In conclusion, the high rate of psychiatric disorders in homeless youth provides clear evidence that the mental health needs of this population are significant. Implications are discussed.