In TRANSFORM three European regions join forces and open up their R&I activities to co-create more responsible approaches to innovation. Lombardy in Italy, Brussels in Belgium and Catalonia in Spain are all leaders in experimenting new pathways for territorial development. TRANSFORM brings them together to design, test and disseminate three sound co-creation methodological frameworks (participatory research agenda setting; design for social innovation; and citizen science). These frameworks will be at the forefront of implementation of Smart Specialisation Strategy (S3). They provide approaches and application areas of responsible and accountable territorial development through new forms of local decision-making. They have also proven beneficial in aligning science, innovation and society, making R&D more responsive to citizens’ needs, concerns and aspirations. The three initiatives will implement a mutual learning process within and beyond Europe, pairing with a parallel co-design exercise in Boston (Massachusetts, US). The work in these three clusters will support and increase co-creation and participatory processes within their R&I ecosystems, both building on existing regional commitments towards transformative opportunities and strengthen the opening effect on the organisations involved. Regional governments involved in TRANSFORM will reflect on, experiment with, learn from and adopt RRI approaches to their R&I policies and actions. Concrete examples of inclusive and sustainable territorial development will be attained, thus providing a set of reliable Policy Recommendations to transforming regional R&I ecosystems towards RRI. TRANSFORM will also be integrated into Strategic Roadmaps for the implementation of RRI within S3, addressed to S3 key players, for maximum benefit across all S3 Thematic Platforms.