Abstract The aim of this paper is to understand how top-down and centrally orchestrated mission-led policies can galvanise action and activities at the local regional level. Mission-oriented innovation policies, as adopted by the European Union (EU) and various national governments, tie top-down prioritisation of societal problems to bottom-up problem-solving capacities. By linking together differ strands of the theoretical literature and evidence, we argue that a critical challenge to make mission-led innovation policies work is to create resonance between (supra)national missions and the daily reality of field-level actors located in strong or weak regions with different problems, capabilities, and institutions. Possibilities for synchronising those two worlds depend on how actors perceive risk and uncertainty, and on how these reframe the salience, credibility, and legitimacy of missions. In order to bridge these gaps, we conceptualise ‘local missions’ as both embedded in, and also rescoping and reshaping, overarching missions, and we discuss possibilities to support them through EU Cohesion policy.