Risk-taking is statistically normative during adolescence, yet is associated with adverse outcomes including substance use. The present study draws the distinction between protective factors (effective for those identified as high risk takers) and promotive factors (effective for all) against substance use, focusing on parental monitoring, school bonding, and sports participation. A total of 36,514 8th and 10th grade participants in the national Monitoring the Future study were included. Although parental monitoring was associated with lower alcohol and marijuana use among all adolescents (i.e., promotive effect), these effects were strongest among the highest risk takers (i.e., protective effect) and females. School bonding was associated with lower levels of both alcohol and marijuana use among all groups of adolescents, but these promotive effects were weak. Sports participation was associated with higher levels of alcohol use among all males and among 8th grade females who did not identify as high risk takers. Despite being a risk factor for alcohol use, sports participation did demonstrate a promotive effect against marijuana use among 10th grade females only, and especially so for high risk-taking females (i.e., protective effect). Overall, these findings suggest that of the three mechanisms studied, parental monitoring emerged as the most promising entry point for substance use prevention and intervention across groups, particularly for females and high risk-taking adolescents.