Substance use disorder (SUD) in adolescence is a serious mental health and social problem with its significant association with morbidity, disability, and mortality. Substance misuse has progressed from the more antisocial, risk-taking, and marginal groups of the population to the mainstream of society and dramatically to younger populations, reinforcing and expanding the boundaries of at-risk populations for SUD. Research in the area of adolescent substance use has expanded significantly over time, and while many studies have contributed to the growth of knowledge in this area, ongoing study remains important. Substance use may be seen through a developmental perspective progressing across adolescence into young adulthood. We have included the most recent studies and research findings on adolescent substance misuse and use disorders in this chapter. The chapter will focus on enhancing knowledge and comprehension of adolescent substance misuse in addressing the following areas: epidemiology, risk-vulnerability, developmental course, and comorbidity. The transitional period of adolescence presents itself as an especially critical and vulnerable time for the onset of substance use with its impact on normal development, future SUD, and society as a whole. Adolescence is a period of major risk for the onset of SUD. The complexity of the risk-vulnerability for substance misuse and use disorders among adolescence is derived from the “addictive shared” effects of multi-domain factors including biological, environmental, interpersonal, socio-cultural, and psycho-behavioral factors. The changing pattern of use through adolescence and high rates of comorbid mental disorders among adolescents with SUD further emphasize the need for better understanding of the epidemiological trend, risk, and comorbidity to inform evidence-based interventions.