Extensive qualitative research in the San Francisco Bay Area in California and in Tucson, Arizona, indicates strong associations between substance abuse and homelessness among American Indians. This article takes a comparative approach to describe and analyze precipitating factors and survival patterns of those who are both homeless and who suffer from substance dependency. Possible precipitating factors presented through case studies consider the complex interaction of childhood fostering or adoption into non-Native families, different types of involuntary institutionalization during youth, and the personal impact of accident, trauma and loss. Coping strategies and keys to survival are examined, including the role of the extended family and close friendships, American Indian and mainstream organizations that offer formal and informal services, the existence of anchor or key households, the helping relationships and sobriety groups among homeless individuals, spirituality, and cultural resiliency.