Alcohol, tobacco, and marijuana are the top 3 substances of misuse among teenagers. According to the Monitoring the Future study,1 marijuana use continues to increase in contrast to tobacco or alcohol use, which has leveled off; currently, more than one-third of 12th graders report having used marijuana in the past year, and 6.5% report using it regularly. Emerging evidence suggests that the adolescent brain is highly vulnerable to exposure to alcohol or cannabis consumption, resulting in proximal and distal impairments in neurocognitive functioning (including memory and intelligence), sensitivity to reward, and emotional regulation. Moreover, deaths in adolescents are largely preventable because most are a result of substance-related motor vehicle accidents and overdose or unintentional poisoning. Substance use disorders (SUDs), especially those that begin during adolescence, have a high likelihood of persisting into adulthood, with associated negative medical, personal, and professional consequences. Pediatric care physicians are well positioned to prevent initiation or curb the progression of substance misuse among adolescents.