Background: We examined the longitudinal trajectory of substance use (binge drinking, marijuana use, and cocaine use) in relation to self-esteem from adolescence to young adulthood. Methods: Generalized estimating equation models were fit using SAS to investigate changes in the relation between self-esteem and each substance use (binge drinking, marijuana use, and cocaine use) from adolescence to young adulthood. Data were drawn from the 3 waves of the National Longitudinal Study of Adolescent Health, a nationally representative sample of middle and high school students in the United States (N = 6504). Results: Self-esteem was a significant predictor for the use of all 3 substances at 15 years of age (ps < 0.001). However, at age 21, self-esteem no longer predicted binge drinking and marijuana use in the controlled model. Conclusions: It appears that self-esteem loses its protective role against substance use except cocaine use as adolescents transition to young adulthood.