This study evaluated sex differences in substance use changes across two transitions: from adolescence (age 17 yrs.) to emergent adulthood (age 23 yrs.), and maturing out from emergent to later young adulthood (ages 28 and 33 yrs.).Four-wave longitudinal data (N = 1004) from adolescence to young adulthood were used and five substance outcomes were assessed (cigarette, alcohol, and marijuana use, heavy drinking episodes (HDEs), and alcohol problems). A longitudinal mixed model tested Sex × Time interactions to determine if sex moderated changes in substance outcomes.Findings supported both increases in substance outcomes from adolescence to emergent adulthood and decreases in substance outcomes from emergent adulthood to later young adulthood. Sex moderated these relationships, with males increasing their use of substances more than females across the transition from adolescence to emergent adulthood. Findings were partially robust across substance outcomes, although sex specificity was indicated for some substance outcomes (e.g., males' greater acceleration than females for HDEs) for the adolescent to emergent adult interval (from ages 17-23 years) and sex differences in maturing out for some outcomes (e.g., females' matured out earlier than males for cigarette and marijuana use).These findings provide support for developmental changes associated with significant increases in substance use during the early twenties and decreases (maturing out) in the late twenties and early thirties. Sex moderated the strength of these relationships and these sex differences may be associated with changes in young adult social roles (e.g., marriage, parenting, and occupational roles).