Context: Counties across the United States must contend with multiple, intertwined threats and costs that defy simple solutions. Decision makers face the necessary but difficult task of prioritizing those interventions with the greatest potential to produce equitable health and well‐being.

Conclusions: To safeguard health and well‐being in a system dominated by tangled threats and costs, the most important priorities for a county cannot be simply inferred from a profile of its relative strengths and weaknesses. Two interventions stood out as the top priorities for almost all the counties in this study, and six others also were important contributors. Interventions directed toward these priority areas are likely to yield the greatest impact, irrespective of the county’s specifics. A significant concentration of resources in a regional portfolio therefore ought to go to these strongest contributors for equitable health and well‐being.

Policy Points:

• Interventions in a regional system with intertwined threats and costs should address those threats that have the strongest, quickest, and most pervasive cross‐impacts.
• Instead of focusing on an individual county’s apparent shortcomings, a regional intervention portfolio can yield greater results when it is designed to counter those systemic threats, especially poverty and inadequate social support, that most undermine health and well‐being virtually everywhere.
• Likewise, efforts to reduce smoking, addiction, and violent crime and to improve routine care, health insurance, and youth education are important for most counties to unlock both short‐ and long‐term potential.

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