This chapter reviews empirical research on risk-factors for adolescent onset of substance use and misuse, with a particular focus on a recent body of literature aimed at understanding the link between early onset substance use, neuropsychological impairment and future addiction risk. The evidence suggests a causal pathway with some studies showing that adolescents might be more sensitive to the neurotoxic effects of substances, which contributes to their heightened addiction vulnerability. While questions remain pertaining to the extent to which cognitive precursors to early onset substance use account for these impairments, the evidence from a few studies suggests that early substance misuse produces some cognitive or emotional processing impairment beyond these premorbid deficits. The possible interaction between premorbid deficits and the effects of substance use on cognitive development might also explain why early onset substance use so rapidly spirals into substance abuse and dependence and provides a strong rationale for preventing early onset substance use, particularly among those at risk. This chapter then reviews the different approaches to drug and alcohol prevention, the evidence-base for current programs and the essential intervention components that lead to beneficial outcomes and high implementation fidelity.