The Helping to End Addiction Long-term (HEAL) initiative of the National Institutes of Health was launched in 2018 to provide scientific solutions to the evolving crisis of opioid misuse, addiction, and overdose. This comprehensive approach includes efforts to develop more effective therapies for managing pain and for treating opioid use disorder (OUD), test effective pain management strategies that limit addiction risk, and implement evidence-based OUD treatment in a variety of settings. Since HEAL was initiated milestones have been achieved including the span of novel nonopioid targets for pain; a standard of care for infants with NOWS; a comprehensive, interoperable data set for pain research that will feed a pipeline of novel therapeutics; and integration of evidence-based treatment into practice for the nonpharmacological management of multiple acute and chronic pain conditions and for the medication-based treatment of OUD. This report outlines other advances HEAL has made since its inception.