Building on the main results from the TSER reports reviewed in the VALICORES project, this survey article focuses on the Knowledge Infrastructure (KI) and on the institutional-spatial dynamics that characterize innovation and knowledge creation/accumulation/diffusion processes within the developing knowledge-based economy and society. Its aim is threefold. Firstly, the paper seeks to disentangle some crucial issues linked to the nature of the KI and the various agents it involves, their patterns of behaviour and forms of interaction, and their roles in knowledge and innovation processes. The second aim is to determine the extent to which institutional and spatial configurations shape knowledge and innovation dynamics in the European context. Finally, the article advances an analytical framework which could help the understanding of the dynamic interplay of institutions, strategies and spatial scales in the structuring and the deployment of the KI.