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Primary care physicians and practice teams increasingly recognize the need to take a role in addressing the growing epidemic of opioid use disorder (OUD) and opioid-related drug overdose deaths, but face considerable challenges in doing so. Through its work supporting practice transformation efforts, sharing innovations, and connecting key sectors within communities, the Network for Regional Healthcare Improvement and several of its member regional health improvement collaboratives have identified innovative ways to support physicians and practice teams in transforming practice in ways that address a spectrum of issues related to opioid use. These strategies include efforts to prevent, identify, and treat opioid addiction, including reducing inappropriate prescribing; improving opioid prescribing safety; compassionately tapering chronic and/or high-dose opioid regimens; appropriately screening for and identifying OUD; initiating treatment with evidence-based medications for OUD within practice settings; and prescribing life-saving naloxone to reverse opioid overdose. By outlining specific initiatives and practice transformation efforts that several regional health improvement collaboratives across the country have implemented to support clinicians and their teams, this article offers examples of how clinicians can get support from collaboratives in their region to implement practice improvement efforts to advance this critically important work.