The aim of this paper is to provide insights into the implications of the European Commission’s smart specialisation agenda in a specific, cross-border context. The paper critically reflects on some of the RIS3 (research and innovation strategies for smart specialisation) agenda’s premises by illustrating its practical implementation in the Upper Rhine area (i.e. Alsace in France and Baden-Württemberg in Germany). The first section revisits not only the smart specialisation concept in itself but also discusses it vis-à-vis the thematic of cross-border regional innovation systems and outlines some implications that it may have for the choice of innovation policy instruments. The second section introduces the specific framework of the Upper Rhine area and outlines possible options for the co-ordination of innovation policies on the basis of a yet to be developed, theoretically possible joint RIS3 strategy. The last section brings together these conceptual and applied perspectives on smart specialisation and outlines suggestions for progressive cross-border integration via regional innovation policies.