Global megatrends-including climate change, food and water insecurity, economic crisis, large-scale disasters and widespread increases in preventable diseases-are motivating a bioregionalisation of planning in city-regions around the world. Bioregionalisation is an emergent process. It is visible where societies have begun grappling with complex socio-ecological problems by establishing place-based (territorial) approaches to securing health and well-being. This article examines a bioregional effort to merge place-based health planning and ecological restoration along the US-Mexico border. The theoretical construct underpinning this effort is called One Bioregion/One Health (OBROH). OBROH frames health as a transborder phenomenon that involves human-animal-environment interactions. The OBROH approach aims to improve transborder knowledge networking, ecosystem resilience, community participation in science-society relations, leadership development and cross-disciplinary training. It is a theoretically informed narrative to guide action. OBROH is part of a paradigm shift evident worldwide; it is redefining human-ecological relationships in the quest for healthy place making. The article concludes on a forward-looking note about the promise of environmental epidemiology, telecoupling, ecological restoration, the engaged university and bioregional justice as concepts pertinent to reinventing place-based planning.