The world is urbanizing rapidly, and many urbanized regions deplete and degrade their environment. The additional polycrisis of climate change, biodiversity loss, epidemics, food insecurity, and reduced water, air, and soil quality asks for a transformational vision for the design and planning of these urban regions. Current planning practices are not able to respond to the complexity of the problems associated with the polycrisis. At the same time, regenerative thinking has not yet been practical enough to be accepted into spatial planning practices and create regenerative regions that can respond to the global polycrisis. This mismatch reinforces the status quo of well-thought-through regenerative frameworks on the one hand and ongoing spatial planning in urban regions on the other. The aim of this study is to create a regenerative framework for regional planning. A range of regenerative frameworks have been analyzed and integrated into one ‘framework of frameworks’, highlighting clusters of attributes describing the ‘what’, ‘when’, ‘how’, and ‘who’ of what needs to happen to create a regenerative world. On the other hand, expert judgement of planning practices in nine urban regions around the world provided insight about the priorities for regional regenerative development. This clarified the ‘what’ and ‘where’ of different aspects of urban planning in the region. Bringing the theoretical frameworks and practical understanding of urban planning together, the regenerative framework for regional planning provides a practical approach for navigating the complexities of creating a regenerative region. It starts by backtracking to the 1st generation city (of first settlements and indigenous understanding of the land). When this equilibrium is found, it is used to create a vision for the 3rd generation city (in which regenerative potentials are fully used). The comparison with the 2nd generation city (a current anthropogenic industrial city) clarifies what must change, how this change can be achieved, and who the agents of change are to make it happen.