Objective: This study examined the effects of leaving home and going to college on changes in the frequency of alcohol use, heavy episodic drinking, and marijuana use shortly after leaving high school. We also examined how protective factors in late adolescence predict post-high school substance use and moderate the effects of leaving home and going to college. Method: Data came from subjects (N = 319; 53% male) interviewed at the end of 12th grade and again approximately 6 months later, as part of the Raising Healthy Children project. Results: Leaving home and going to college were significantly related to increases in the frequency of alcohol use and heavy episodic drinking from high school to emerging adulthood but not to changes in marijuana use. Having fewer friends who used each substance protected against increases in the frequency of alcohol use, heavy episodic drinking, and marijuana use. Higher religiosity protected against increases in alcohol- and marijuana-use frequency. Higher parental monitoring protected against increases in heavy episodic drinking and moderated the effect of going to college on marijuana use. Lower sensation seeking lessened the effect of going to college on increases in alcohol use and heavy episodic drinking. Conclusions: To prevent increases in substance use in emerging adulthood, interventions should concentrate on strengthening prosocial involvement and parental monitoring during high school. In addition, youths with high sensation seeking might be targeted for added intervention.