The EU initiative for “Smart Specialisation Strategies” (S3) is animating the policy debate thanks to an interesting and innovative approach. However, this rapid success has left some mismatches from theory to practice that have emerged after the first round of implementation, and related considerations. To reflect on the S3 notion, we discuss the cases of Milan and Brussels which, in our view, question relevant theoretical elements: two advanced urban areas with entirely different institutional and spatial settings facing structural challenges and significant opportunities to keep a high level of competitiveness. This article aims to compare these two cases around four analytical dimensions: the multi-scale aspect of issues addressed; the relationships between the urban core and the surrounding areas; the possibility to govern the structural changes in the economy leading to jobs creation; and the capacity to locally embed economic development. We conclude arguing that time and space are fundamental variables to understand the dynamics leading to a ‘successful’ S3 implementation regarding the replicability of experiences associated to the scale of intervention, the long-term effects and risk-taking attitudes.