The spatial dynamics of regional innovation cannot be explained by the locational decisions of firms and workers alone. Globalization continues to put primacy on the relationship between public policy and the economic competitiveness of regions. Policy makers across the Organisation for Economic Co-operation and Development (OECD) countries are preoccupied with ways to encourage knowledge-intensive regional growth, not just in places where it is already well established but also in those struggling for reinvention. Largely resourced by public policy, a complex mix of formal and informal institutions shapes the context in which much economic activity occurs. This chapter brings institutions ‘in’ to the discussion of regional economic development, drawing analytical attention to the multi-level nature of economic innovation and how the interplay among different levels of government and multiple public and private sector actors shapes regional development trajectories. The three intersecting themes of governance, scale and agency provide an analytical framework for examining the ways in which ‘top-down’ multi-level institutional structures and ‘bottom-up’ associational governance dynamics enable and constrain regional restructuring and innovation. Following a conceptual overview of the New Regionalism, we offer brief policy illustrations of these ‘ideas in action’, highlighting selected regional innovation programmes underway in the European Union, the United States, and Canada, three jurisdictions long known for government engagement with problems of regional decline and renewal.