This paper considers the recent developments in regional innovation policy pertaining to the smart specialisation agenda from the perspective of a peripheral and semi-autonomous region – Wales in the UK. Through a case study of innovation policy developments in Wales over the past 20 years, and also a consideration of extant literature pertaining to regional innovation policy and smart specialisation, this paper finds a number of issues or shortcomings in the current predominant smart specialisation approach. These are traced back to the strong regional innovation system logic existing in European policy; a number of unresolved theoretical problems that could undermine the efficacy of innovation policy are identified. Both conceptual and rhetorical issues with the concept of the region are highlighted, and questions are asked about the applicability and tenability of smart specialisation approaches in semi-autonomous, cross-border regions, and for policymakers operating in circumstances of multi-level governance. This paper illustrates how such regions provide us with a lens or alternative perspective through which to reconsider our predominant theoretical and practical policy approaches, and highlights a number of potential problems with smart specialisation as it is applied in a diverse range of regional settings.