Older adolescence represents a critical period of brain development whereby the prefrontal cortex, responsible for higher level thinking and emotional regulation, is under construction. During this period, the brain is wired to underestimate risk and overestimate pleasure, which primes young people towards risky, pleasure-oriented experiences. Substance use during this time can hinder brain maturation and lead to development related disorders. However, young people are the most likely to drink at risky quantities, use cannabis, MDMA and cocaine in the previous 12 months than any other age group. Despite this, there are no validated, age-appropriate prevention programs targeting school leavers, which leaves a group of young people to navigate a landscape where drug use is the most common, without formal support. Drug and alcohol prevention programs should be developed for this age group that combine features of universal prevention programs and targeted intervention programs to support the wider range of drug use behaviours relevant to this older audience. This article outlines potential evidence-based strategies that programs could focus on in the future. [Debenham J, Newton N, Birrell L, Askovic M. Alcohol and other drug prevention for older adolescents: It's a no brainer. Drug Alcohol Rev 2019;38:327-330]