Substance use in young people (aged 10–24 years) might disrupt key periods of transition that occur as the adolescent brain undergoes cognitive and emotional development, and key psychosocial transitions are made. Adolescence is the peak time for initiation of substance use, with tobacco and alcohol usually preceding the use of illicit drugs. Substantial variation is noted between countries in the levels, types, and sequences of substance use in young people, indicating that a young person's use of substances depends on their social context, drug availability, and their personal characteristics. The Global Burden of Disease (GBD) 2013 study suggests that the burden attributable to substance use increases substantially in adolescence and young adulthood. In young men aged 20–24 years, alcohol and illicit substance use are responsible for 14% of total health burden. Alcohol causes most health burden in eastern Europe, and illicit drug burden is higher in the USA, Canada, Australia, New Zealand, and western Europe. Large gaps exist in epidemiological data about the extent of drug use worldwide and much of what we know about the natural history of substance use comes from cohort studies in high-income countries undertaken decades ago, which hinders effective global policy responses. In view of the global epidemiological transitions from diseases of poverty to non-communicable diseases, the burden of disease and health risks among adolescents and young adults is likely to change substantially, in ways that will no doubt see substance use playing an increasingly large part.