Background: Anthropologists are beginning to translate insights from ethnography into tools for population studies that assess the role of culture in human behavior, biology, and health. Aim: We describe several lessons learned in the creation and administration of an ethnographically-based instrument to assess the life course perspectives of Appalachian youth, the Life Trajectory Interview for Youth (LTI-Y). Then, we explore the utility of the LTI-Y in predicting depressive symptoms, controlling for prior depressive symptoms and severe negative life events throughout the life course. Subjects and methods: In a sample of 319 youths (190 White, 129 Cherokee), we tested the association between depressive symptoms and two domains of the LTI-Y life course barriers and milestones. Longitudinal data on prior depressive symptoms and negative life events were included in the model. Results: The ethnographically-based scales of life course barriers and milestones were associated with unique variance in depressive symptoms, together accounting for 11% of the variance in this outcome. Conclusion: When creating ethnographically-based instruments, it is important to strike a balance between detailed, participant-driven procedures and the analytic needs of hypothesis testing. Ethnographically-based instruments have utility for predicting health outcomes in longitudinal studies. © 2009 Informa UK Ltd.