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This article analyses the “Europe of the Regions” as a project that aims at building up regions as (new) political subjects within the European Union (EU) system. Regions have attempted to become not only political actors with capacity to have an influence but subjects with decision-making power. The article, after describing the evolution of the regional agenda from Maastricht to the Lisbon Intergovernmental Conference (1992-2007), turns to assess first of all the multi-level governance (MLG), the political science dominant approach on the analysis of EU-sub-state relations, and secondly the Intergovernmental Relations approach (IR). The article argues that the IR approach can cast new light over the issue. The conclusions show that the IR approach has an explanatory capacity, and clarify the obstacles that the EU regions have to face in their strategy for a structural and legal recognition of their role within the EU. Similarly and given that the governments of the member-state do not provide for domestic mechanisms that project the regional interests into the EU spheres, it seems appropriate to examine some of the regional activities towards the EU as subnational foreign policies.