This volume presents new 2021 findings from the U.S. national Monitoring the Future follow-up (panel) study concerning substance use among the nation's college students and adults from ages 19 through 60. We report 2021 prevalence estimates on numerous illicit and licit substances, examine how substance use differs across this age span, and show how substance use and related behaviors and attitudes have changed over the past four decades. The panel study now has over 108,000 individuals, with approximately 28,500 surveyed each year including young adults ages 19 to 30 and adults ages 35 to 60. These data, gathered on national samples over such a large portion the lifespan, are extremely rare and can provide needed insight into the epidemiology, etiology, and life course history of substance use and relevant behaviors, attitudes, and other factors. The current report is the latest in a series of publications dating back to 1986. [For "Monitoring the Future National Survey Results on Drug Use, 1975-2021: Volume 1, Secondary School Students," see ED619855. For "Monitoring the Future National Survey Results on Drug Use, 1975-2020. Volume II, College Students & Adults Ages 19-60," see ED615085.]