This chapter aims to better understand the implications of transformative change for regional innovation systems (RIS) research and policy by looking more closely into processes of structural change within coal regions against a context of transitions to a low-carbon future. Case studies of Germany’s Ruhr and Australia’s Latrobe Valley are used to demonstrate the challenges in implementing regional innovation policies under conditions of fundamental uncertainty. In the absence of regional innovation system structures and institutions, there is first and foremost a need for organisational and institutional innovation to arrive at working configurations of actors, networks and institutions that could act as proto- or ‘pop-up’ innovation systems. This chapter aims to shed some light on how to approach such processes. It argues that policymakers and researchers should explicitly acknowledge the experimental nature of RIS policy and conceptualize RIS policy development and implementation as a series of governance experiments.