Opioid overdose deaths remain a threat to patient safety. Information about how overdose deaths are nationally distributed is critical to inform prevention efforts. This robust analysis examined all drug overdose deaths in the United States over a 38-year period. Drug overdoses began increasing exponentially long before the opioid prescribing boom in the mid-1990s and continue to rise in this way. Demographically distinct subepidemics of prescription opioid, synthetic opioid, and stimulant use all contribute to drug overdose deaths as a whole. The authors speculate about what factors other than opioid prescribing might drive escalating substance use-related deaths. An Annual Perspective and a PSNet perspective provide further insights into how safety efforts can reduce opioid-related harm.