Extraordinary focus by all segments of society is required to respond to the nation’s opioid crisis. Now is the time to channel the efforts of the scientific community to deliver effective—and sustainable—solutions to this formidable public health challenge. Recognizing this opportunity, Congress added $500 million to the base appropriation of the National Institutes of Health (NIH), starting in fiscal year 2018.1 The NIH will invest these much-needed resources to support science that advances national priorities for addiction and pain research2 with a bold new trans-NIH initiative called Helping to End Addiction Long-term (HEAL).3 In this Viewpoint, we outline the initial components of this cross-cutting, interdisciplinary program.