Increasingly frequent extreme weather conditions due to climate change concomitant with unsustainable historical resource use and management practices create the perfect storm – threatening our livelihoods, well-being and environment. A transition towards resilience requires that we simultaneously address social inequalities and implement cross-sectoral innovations to build social, economic and environmental resilience to extreme events. Together, Regions4Climate partners commit to addressing current and forecasted climate change-related challenges and building more resilient European communities within an innovative socially engaged, citizen-driven paradigm. We aim to develop smarter, more inclusive, more resilient regional ecosystems through cross-sectoral innovation jointly created with stakeholders, by and for people. The development and implementation of cross-sectoral strategies that incorporate combinations of social, technological, digital, business, governance and environmental solutions to common climate resilience challenges is at present constrained by knowledge deficits and uncertainties, as well as science-policy-stakeholder gaps. Regions4Climate will bridge these gaps and address existing uncertainties by further developing, adapting and integrating state-of-the-art technical know-how, innovative tools and collaborative practices to support transparent, evidence-based risk and vulnerability analyses and robust decision-making processes. We will utilise system dynamic modelling to understand relationships among and trade-offs between different resilience innovations, providing tools for informed decision-making tailored to engage stakeholders and support European regions and communities exposed to significant climate change impacts. New scientific insights, along with a framework of interoperable tools, methodologies and demonstrated solutions will enable European regions to develop their own resilience plans and transformative adaptation pathways.