Although three centuries of industrialisation and growth have led to unimaginably better lives for most people, economic and health outcomes differ widely across places, both between and within polities. We suggest that understanding these differences requires considering the role of ‘placeless’ agents in shaping places – here, subnational regions. Prior economic development and globalisation have rewarded and empowered placeless agents: firms, people and institutions which rely for wellbeing, identity and profits not on a specific place, but rather on a type or types of place. Their mobility and lack of embeddedness means interactions with specific places is functionally narrow, voluntary, self-interested, and hence potentially problematic for embedded actors, and for the health and viability of the places within which they operate. We look to operationalise this concept by developing notions of economic, socio-cultural and civic placelessness, and reflect on how the power of the placeless may shape local responses to critical challenges.