We used a life stress framework to examine linkages between distal or primary stressors (e.g., child abuse) and proximal or secondary stressors (e.g., street victimization) and their association with substance use among 150 youth experiencing homelessness in the Midwestern United States. Results revealed that numerous primary stressors such as number of times youth ran from home and number of foster care placements were associated with secondary stressors, such as anxiety, total duration of homelessness, and street victimization. Only street physical victimization (e.g., been beaten up since leaving home) was associated with greater substance use. Our findings provide a more holistic picture of both distal and proximal life stressors that these young people experience and reveal the complexity of issues that service providers must acknowledge when working with this population.