The high rates of substance use among American adolescents are challenging; however, runaway youth are at particularly high-risk for substance use. Runaway youth utilizing two service sectors, emergency crisis shelters and juvenile detention centers, were recruited to evaluate differences in risk factors associated with substance use. Findings demonstrate that youth admitted to juvenile detention (n = 121) had proportionally higher levels of problem behaviors, including substance use, than youth admitted to shelter services (n = 156). Both groups of youth have significantly higher levels of substance use than national estimates. The most significant risk factor for alcohol and marijuana use among youth in both groups was using other substances. Addressing issues of substance abuse among runaway youth must be a prime objective for future research and treatment for this high-risk population.