Why does substance use escalate and become problematic for some people, but not others? Adolescence and young adulthood represent critical windows of risk, when substance use experimentation is common and patterns of use are shaped. Understanding and addressing the key drivers of substance use escalation is essential for timely, effective prevention and early intervention. Drawing on data from large school based prevention trials, this presentation highlights how substance related harm can be reduced by addressing key social, contextual, and mental health factors early in the life course. These modifiable factors also have important implications for longer term substance use trajectories and recovery. In particular, mental health problems such as anxiety can exacerbate substance use and undermine recovery. Evidence from clinical trials shows that recovery outcomes are improved by early intervention and treatment approaches that address the interconnection between mental health and substance use concerns. In addition to synthesising up to date evidence, the presentation will connect attendees with prevention, early intervention, and treatment approaches that can alter substance use trajectories to improve health outcomes.