Due to several genetic, physiological, and environmental risk factors, adolescents with ADHD are at increased risk of using substances and developing an addiction to alcohol, nicotine, cannabis, and other drugs. However, this increased risk can be significantly reduced by appropriately diagnosing and treating ADHD. While substance use can often mimic symptoms of untreated ADHD, it can also worsen ADHD symptoms and interfere with treatment. In teens with ADHD, and co-occurring substance use problems, both matters should be addressed simultaneously. While stimulant medications for the treatment of ADHD carry risks of misuse or diversion, there are several ways for families, schools, and health providers to ensure that adolescents with ADHD and substance use problems receive safe and effective treatment. In this chapter, we provide an overview of substance use problems in youth and how they may differ in adolescents with ADHD. We then discuss several strategies for the prevention and treatment of substance use problems in adolescents with ADHD.