The United States drug overdose epidemic has reached an all-time high, with 2020 provisional mortality data indicating that over 90,000 lives were lost to drug overdose in the 12-months ending in December 2020. The overdose epidemic has evolved over time with respect to the substances involved in overdose deaths and also with respect to the geographic distribution and epidemiology of deaths involving specific substances. Thus, a nimble approach to addressing the epidemic and preventing future overdoses is needed. CDC’s response to the overdose epidemic supports implementation efforts at the state and local levels, where partners can better detect and respond to the evolving drug overdose landscape and implement prevention measures that meet their needs. CDC’s framework for responding to the overdose epidemic focuses on five areas: (1) conducting surveillance and research; (2) building state, local and tribal capacity; (3) supporting providers, health systems and payers; (4) partnering with public safety; and (5) empowering consumers to make safe choices. Central to informing the implementation of evidence-based strategies to prevent drug overdose is rigorous research that undergirds the evidence. This Commentary describes recent investments in overdose prevention research and outlines opportunities for ensuring that future research efforts allow for the flexibility necessary to effectively respond to the continually evolving epidemic.