Background: Despite high rates of substance use among homeless youths, little is known about the interaction of substance-use risk and protective factors. Further, limited research exists on substance use by school-attending homeless youths, as extant studies have relied on street- and shelter-based samples. Objective: The purpose of this study was to examine how risk and protective factors influence school-attending homeless youths' substance use as well as how protective influences can mediate and moderate the impact of risk factors on substance use. Empirical precedents on adolescent substance use and social capital theory were used to construct a theoretical model. Methods: Structural equation modeling was used to examine the relationships among risk and protective factors associated with substance use. The theoretical model was tested with a representative sample of 2,146 high-school-attending homeless youths from the 2007-2008 California Healthy Kids Survey dataset. Three hypotheses were tested to examine the direct effects of gang involvement, partner abuse, truancy and adult support on substance use as well as both the mediating and moderating effects of adult support. Results: Greater substance use was associated with gang membership, partner abuse and truancy. Lower levels of substance use were associated with higher levels of adult support. Additionally, adult support acted as both a mediator and moderator between the hypothesized risk factors and substance use. Conclusions: Findings highlight the mediating and moderating effects of adult support on substance-use risk factors. Future longitudinal research is needed to illuminate the causal pathways between substance-use risk factors, adult support, and actual use.