How to organize clusters as local agents of transformative change, i.e. players that actively contribute to systemic sustainability transitions anchored in territories? We take a meta-organizational approach to the design of clusters for sustainability. We argue that achieving meta-organizational 'responsible actorhood' is a crucial condition for clusters to act as local agents of transformative change. Responsible actorhood allows to address the issues of lack of answerability, path dependency towards growth and labor resistance. Responsible actorhood involves 1) developing mechanisms to ensure 'metaorganizational accountability', 2) nurturing 'transformative mediated reflexivity' about technological ruptures and ecological performance in a public-centric approach and 3) enabling 'negotiated professional restructuring' to establish new knowledge processes at work. We contribute to the literature on clusters and STI policy, and to the metaorganization literature. Our work also has policy and practical implications for the design and steering of eco-industrial clusters.