In the DSM-5-TR, post-traumatic stress disorder is characterized by intrusive symptoms, persistent avoidance, alterations in cognitive and emotional states, and heightened arousal responses that arise following exposure to significant traumatic events. This chapter explores the relationship between this disorder and substance use during adolescence, addressing clinical, neurobiological, and psychosocial factors. Studies indicate that adolescents with post-traumatic stress disorder frequently exhibit neurobiological alterations in brain regions involved in emotional processing and stress regulation, as well as cognitive biases that favor the recall of threatening information. The disorder is also strongly associated with psychiatric comorbidities, such as depression and anxiety disorders, which may exacerbate substance use as a means of alleviating emotional distress. The chapter further discusses how traumatic experiences can potentiate substance use during this developmental stage, emphasizing the importance of integrated and preventive psychosocial interventions to address this complex intersection.