What is already known about this topic? From 1999 to 2015, the drug overdose epidemic resulted in approximately 568,699 deaths. In 2015, 52,404 drug overdose deaths occurred; 63.1% (33,091) involved an opioid. From 2014 to 2015, the age-adjusted opioid-involved death rate increased by 15.6%; the rapid increase in deaths was driven in large part by synthetic opioids other than methadone (e.g., fentanyl). What is added by this report? In 2016, there were 63,632 drug overdose deaths in the United States. Opioids accounted for 66.4% (42,249) of deaths, with increases across age groups, racial/ethnic groups, urbanization levels, and multiple states. Age-adjusted death rates for overdoses involving synthetic opioids other than methadone doubled from 2015 to 2016, and death rates from prescription opioids, heroin, cocaine, and psychostimulants also increased. What are the implications for public health practice? There is an urgent need to implement a multifaceted, collaborative public health and public safety approach. Building on existing resources, more rapidly available and comprehensive surveillance data are needed to track emerging drug threats to guide public action to prevent and respond to the epidemic through increased naloxone availability, harm reduction services, linkage into treatment (including medication-assisted treatment), safe prescribing practices, and supporting law enforcement strategies to reduce the illicit drug supply.