There is a clear acknowledgment in the literature of the importance of developing regional innovation strategies to build competitive advantages. However, the concept remains fuzzy in terms of its limits and contents applied to the territorial field. This paper analyses one concrete type of territorial strategy that is currently being disseminated by the European Commission for regional development: the smart specialisation strategy (S3). Specifically, this paper analyses the aspects that remain under discussion and are opened to greater development and precision under the smart specialisation concept. The focus is on two dimensions: the content of the strategy and the process of the strategy (the “what” and the “how and who” of the strategy). By analysing the evolution of S3 since the 1980s and three cases of S3 based on research and development (R & D) in the Basque Country, the paper emphasises the convenience of adopting a broad definition of S3 and the different roles of the government depending on the existing capabilities in the region. Moreover, the paper indicates that it is preferable to simultaneously and not consequentially develop the necessary scientific and technological capabilities and the generation of a shared vision of the S3 strategy in an entrepreneurial process.