Adolescence is an important period of risk for substance use initiation and substance use-related adverse outcomes. 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. Logistic regression and Joinpoint analyses were used to assess 2009-2019 trends. Prevalence of current and lifetime substance use by demographics, frequency of use, and prevalence of co-occurrence of selected substances among students reporting current prescription opioid misuse are estimated using 2019 data. Multivariable logistic regression analysis was used to determine demographic and substance use correlates of current prescription opioid misuse. Current alcohol, lifetime cocaine, methamphetamine, heroin, and injection drug use decreased during 2009-2019. Lifetime use of synthetic marijuana (also called synthetic cannabinoids) decreased during 2015-2019. Lifetime marijuana use increased during 2009-2013 and then decreased during 2013-2019. In 2019, 29.2% reported current alcohol use, 21.7% current marijuana use, 13.7% current binge drinking, and 7.2% current prescription opioid misuse. Substance use varied by sex, race/ethnicity, grade, and sexual minority status (lesbian, gay, or bisexual). Use of other substances, particularly current use of alcohol (59.4%) and marijuana (43.5%), was common among students currently misusing prescription opioids. 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.