Previous research indicates a positive link between youth runaway episodes and the likelihood of homelessness in later adolescence and early adulthood. An adolescent's decision to run away from home often accompanies depressive symptomology compared with stably housed youth. The present study used a large, nationally representative sample of 8,560 youth to identify links among runaway behavior, changes in depressive symptomology during the transition from adolescence to emerging adulthood, and homelessness. Results suggest that running away during adolescence is linked with later homelessness across depressive symptom classes. In fact, even a single runaway episode as a teenager tripled the odds of reporting homelessness by young adulthood. However, the magnitude of the association varies based on depressive symptom trajectories. Adolescents reporting high levels of depressive symptomology that increased over time were 6 times more likely to experience homelessness, compared with youth with consistently low depressive symptoms. Interestingly, among participants who reported never running away, this same high/increasing depressive symptoms group were less likely to report homelessness than were peers with consistently low depressive symptoms. These findings point to a potential resiliency process among youth in this category that needs to be further explored to identify differences in youth with poor mental health who leave home verses those who remain stably housed.