Substance use is highly prevalent among homeless, street-involved young people. Societal estrangement is often associated with substance use, particularly among this population. The current study sought to identify four domains of social estrangement (disaffiliation, human capital, identification with homeless culture, and psychological dysfunction) in relation to alcohol and drug addiction. Homeless young adults were recruited from three disparate urban areas: Los Angeles, CA (n = 50), Austin, TX (n = 50) and St. Louis, MO (n = 46) using comparable research methods and measurement instruments. Findings demonstrated that variables measuring psychological dysfunction and homeless culture predicted alcohol addiction, while institutional disaffiliation and homeless culture predicted drug addiction. Findings affirm distinct patterns of estrangement related to alcohol compared to drug addiction. Understanding these features and the heterogeneity of this population has strong potential for assisting development of programs targeting substance use among this underserved population. (Contains 4 tables.)