Research and Innovation Strategies for Smart Specialisation (RI3s) were launched within the EU Cohesion policy for the 2014-2020 period. Smart Specialisation is an experimental policy approach requiring the identification of strategic areas of intervention through both analytical methods and stakeholders participation. Such an approach implies a move from a ‘generic’ to a ‘place-based’ regional development policy (McCann & Ortega-Argilés, 2015). Since the introduction of RIS3, governance has been considered an important pillar of the strategy. However, the scientific discussion on governance has largely stemmed from a theoretical perspective, without taking into account the underpinning administrative framework and constraints. This paper fills this gap by comparing the governance structures of two regions from the south of Europe: Extremadura, Spain and Puglia, Italy. Both are classified as less-developed regions, both belong to member states that devolve significant administrative competences to regions and both have suffered significantly from the financial crisis of the last decade. The paper discusses the challenges in the multi-level and multi-layer governance structure, building on the literature on innovation systems and economic geography. The paper argues that unless the debate on RIS3 governance (and on Smart Specialisation in general) is grounded in the reality of public administration rules and practices, it impossible to advance in our understanding.