The evolving US opioid crisis is complex and requires myriad different interventions. These include reducing opioid overprescribing and curtailing the supply of illicit opioids, overdose rescue interventions, and treatment and recovery support services for those with opioid use disorders. To date, more distal primary prevention strategies that have an evidence base are underutilized. Yet, the impact of early environments on later substance use disorder risk is increasingly well understood, including knowledge of the mechanistic linkages between brain development and subsequent risk behaviors. Applying this developmental framework to prevention shows promise, and some middle-school interventions have demonstrated significant reductions in prescription opioid misuse. Reducing these risks of initial misuse of opioids may be the "ounce of prevention" that makes a substantial difference in a society now reeling from the worst drug crisis our country has seen. The challenge is to continue to develop and test promising distal interventions and to support implementation fidelity through frameworks that ensure their cultural appropriateness and sustainability. In addition, research is needed to develop new prevention strategies for adults, including patients with pain at risk for transitioning from prescription to illicit opioids.