How to organize clusters as local agents of transformative change, i.e. players that actively contribute to systemic sustainability transitions anchored in territories? Recent literature on Transition Studies, and more specifically on Science and Technology Innovation (STI) Policy, argues that a new frame of STI policy is needed, one that focuses on transformative change, experimentations and deliberative governance (Köhler et al., 2019; Schot & Steinmueller, 2018). In what they call the third frame of STI, clusters tend to be somewhat overlooked, as an outdated policy instrument of the 80s. Yet, their geographical omnipresence in Europe and in the rest of the world makes them important tools that need to be not only integrated in transition strategies but also strengthened or redesigned for this very purpose. In this chapter, we investigate under which conditions clusters can provoke system level transformative change for sustainability transition. Bridging industrial ecology literature and Science and Technology Innovation policy, we take a meta-organizational lens on the design of eco-industrial clusters for sustainability. We argue that ‘responsible actorhood’ of clusters is a key organizational condition for clusters to act as local agents of transformative change. We develop ‘responsible actorhood’ around three key dimensions which are needed to ‘meta-organize’ clusters, that is to say to design the industrial system at the meta-organizational level, for transition purposes: 1) gaining ‘meta-organizational accountability’, 2) fostering ‘transformative mediated reflexivity’ about technological ruptures and ecological performance and 3) ‘negotiated professional structuration’ to establish new knowledge processes at work. We contribute to both the literature on clusters and STI policy on the one hand, and to the meta-organization literature on the other hand. Our work also has policy and practical implications for the design and steering of eco-industrial clusters, in particular in other settings than clusters based in developed countries.