In response to the increase in opioid deaths, the Centers for Disease Control and Prevention (CDC) released the Guidelines for Prescribing Opioids for Chronic Pain in 2016, with an update released in 2022. This study reports on the CDC Opioid QI Collaborative which was launched to identify successful evidence-based strategies for implementing the guidelines. The challenges and strategies described in the publication can be used by health systems to accelerate implementation of the guidelines.