This article involves a conceptual evaluation of a large-scale innovation policy experiment—so-called smart specialization strategies (S3s)—that took place within the framework of the European regional cohesion programs between 2011 and the present. The goal is to provide a collection of reflections offering a wealth of lessons and information regarding the capacity of regional governmental agencies and other actors involved in the innovation system to implement a mission-oriented research and development support program and regarding the institutional and cultural conditions that can facilitate its practical application. In the first section, I briefly review the fundamentals of S3s. In the second section, I propose a framework for the identification of mission-oriented policies and I explain how S3 fits into this category. The following section shows how this policy represents a break with the policies that have long dominated the regional policy landscape. The fourth section describes the designing of this policy whose objective is to make strategic choices and decentralization of information and initiatives compatible. And finally, the last section reports on the emerging institutional forms that seem to facilitate the putting into practice of this design.