Since its development in the 1990s, the Regional Innovation Systems (RIS) approach has attracted considerable attention from economic geographers, innovation scholars and policy makers. The RIS approach figures prominently in the scientific discourse about the uneven geography of innovation and the factors that shape the knowledge generation and innovation capacities of regions. The aim of the chapter is to reflect on the emergence of the RIS approach, the current debate as well as future challenges. This chapter is guided by four overarching research questions: What are the origins and theoretical foundations of this approach? What has the RIS approach contributed to innovation studies and economic geography? What are the implications for innovation policy? And what are the recent lines of research and key research challenges in the future? The authors argue that the contributions of the RIS approach have been substantial. Still, the approach has often been applied in a rather static way, more as a heuristic than a coherent theory. The key challenges for current and future research therefore are to move towards a more theory-based, dynamic perspective on RIS, dealing with new path development and the transformation of RIS.