Moving from high school into young adulthood is a critical developmental transition, a time of both continuity and discontinuity in health and well-being. How well one negotiates this transition, as evidenced by one's course of well-being and substance use, depends in part on historical cohort, gender, and life-path. Using U.S. national panel data from 17 consecutive cohorts from the Monitoring the Future study, this paper examines age-related change in well-being and substance use during the first four years following high school. It examines whether the changes varied as a function of cohort group, gender, and life-path group. Findings show that well-being and substance use increased during the transition to young adulthood. Although there were no overall differences in well-being among the three cohort groups, findings show that the course of self-efficacy and fatalism during the transition differed somewhat among the cohorts. Men reported higher levels of well-being and substance use, except for cigarettes, than women. Overall differences in well-being and substance use were found across the life-paths. Limitations of the study and future directions for research are also discussed. (Contains 9 tables, 21 figures, and 68 references.) (MKA)