To examine youth substance use trends and patterns, CDC analyzed data from the 2009–2019 Youth Risk Behavior Survey. This report presents estimated prevalence of current (i.e., previous 30-days) marijuana use, prescription opioid misuse, alcohol use, and binge drinking and lifetime prevalence of marijuana, synthetic marijuana, cocaine, methamphetamine, heroin, injection drug use, and prescription opioid misuse among U.S. high school students. Findings highlight opportunities for expanding evidence-based prevention policies, programs, and practices that aim to reduce risk factors and strengthen protective factors related to youth substance use, in conjunction with ongoing initiatives for combating the opioid crisis.