During puberty, when young people are completing their education, transitioning into employment, and forming longer-term intimate relationships, a shift in emotional regulation and an increase in risky behaviour, including substance use, is seen. This Series paper considers the potential effects of alcohol, tobacco, and illicit drug use during this period on: social, psychological, and health outcomes in adolescence and young adulthood; role transitions, and later health and social outcomes of regular substance use initiated in adolescence; and the offspring of young people who use substances. We sourced consistent support for causal relations between substance use and outcomes and evidence of biological plausibility from different but complementary research designs. Many adverse health and social outcomes have been associated with different types of substance use. The major challenge lies in deciding which are causal. Furthermore, qualitatively different harms are associated with different substances, differences in life stage when these harms occur, and the quality of evidence for different substances and health outcomes varies substantially. The preponderance of evidence comes from a few high-income countries, thus whether the same social and health outcomes would occur in other countries and cultures is unclear. Nonetheless, the number of harms that are causally related to substance use in young people warrant high-quality research design interventions to prevent or ameliorate these harms.