The pandemic has worsened an existing drug overdose crisis that claimed the lives of more than 81,000 people in the U.S. from May 2019-June 2020. As the Biden-Harris administration firms up and implements its proposed response to the opioid epidemic, this brief provides evidence-based recommendations to consider. We focus our recommendations on the evidence and our experience in three areas: reducing the demand for opioids through policies that increase access to prevention, treatment, and recovery services; reducing the harms from opioid use through strategies that reduce morbidity and mortality; and reducing the supply of opioids through opioid stewardship that limits prescribing by the medical community and promotes adequate pain management. We also address the accountability of the pharmaceutical industry in contributing to the crisis and recommend ways to target settlement funds for maximal impact on the communities most affected.