Adolescents are defined as teenagers between 12 and 17 years old. This group is composed of nearly 13% of the United States population, and nearly half have tried an illicit drug by the time they have completed high school. One in eight teenagers has used an illicit drug in the last year (NDAS). While adolescents tend to partake in a variety of substances, alcohol, marijuana, and nicotine remain dominant. Psychosocial environmental factors contribute to this use, and ingestion can alter brain chemistry and development. In this chapter, we will review normal brain development, biological and psychosocial risk factors, effects of substance use, and the most common substances used by adolescents.