This chapter examines the relationship between disruptive, impulse-control, and conduct disorders and substance use during adolescence, focusing on diagnostic criteria, prevalence, neurobiological, and neuropsychological aspects as outlined in the DSM-5-TR. The etiology of these conditions is multifactorial, involving genetic predispositions, neurobiological characteristics, and social factors such as histories of neglect and physical or emotional adversity during development. Research indicates that these challenges significantly increase the risk of substance use, with behaviors such as conduct-related difficulties often preceding the onset of substance use and subsequent substance-related issues. On a neurobiological level, difficulties in processing punishment and rewards and impaired cognitive control are frequently observed. Individuals may exhibit reduced sensitivity to punishment, lower reactivity to rewards, and challenges in executive functioning. Neuropsychological studies have shown that adolescents with oppositional defiant behavior often display considerable difficulties in executive functioning and are frequently diagnosed with additional mental health conditions, including anxiety and depression, which complicate family and social dynamics. Substance use in these adolescents is often shaped by environmental and sociocultural factors that hinder the development of self-regulation and personal boundaries. These young people are particularly vulnerable to peer influence and may turn to substances as a coping strategy for managing emotions such as anger and frustration. The chapter concludes by stressing the importance of integrated psychosocial interventions that address both behavioral challenges and substance use, aiming to improve outcomes for adolescents facing these issues.