This chapter explores the connections between mental health and substance use during adolescence. It presents the concept of adolescence based on a biopsychosocial model, addressing its history and the influence of social, cultural, and political-economic contexts. A critical review of the conceptions of adolescence is conducted, highlighting the shift from stigmatization to a socio-historical understanding, alongside providing global epidemiological data on mental health indicators. The chapter then details the development of the neuro-hormonal system and the neurobiology of adolescent behavior, including aspects of puberty, brain maturation, and the refinement of cognitive functions. Regarding substance use, the chapter presents epidemiological data and diagnoses of substance use disorders and associated comorbidities, emphasizing common factors and specific psychological disorders in adolescents. The scientific and social relevance of this chapter lies in its potential to inform the formulation of interventions and preventive strategies tailored to this population, ultimately aiming to improve mental health outcomes and reduce the risk of substance-related issues among adolescents.