This research tested how the effect of parental emotional and instrumental support on substance (tobacco, alcohol, and marijuana) use in adolescents is mediated. Data were from a sample of 1,702 adolescents surveyed between the 7th and 9th grades. Parental support was inversely related to substance use, and stress-buffering interactions were found at all assessment points. Structural modeling analyses indicated the effect of support was mediated through more behavioral coping and academic competence and less tolerance for deviance and behavioral undercontrol; these mediators were related to negative life events and deviant peer affiliations. Multiple-group analyses suggested buffering effects occurred because high support reduced the effect of risk factors and increased the effect of protective factors. Implications for the theory of social support effects and resilience mechanisms are discussed.