The Joint Research Centre of the European Commission provides support to selected slow growth and less developed regions in the implementation of their Research and Innovation Strategies for Smart Specialisation (RIS3). In addition to the envisaged impacts in these regions, this work also aims to generate wider lessons for RIS3 implementation across the EU. This article describes the approach and key outcomes of this RIS3 support activity in the Greek Region of Eastern Macedonia and Thrace. Focused on the engagement of stakeholders across the region, this activity has sought to catalyse the entrepreneurial discovery process in the region, identifying and developing ideas and partnerships for research and innovation projects. It has examined the development of technical and administrative capacities necessary to advance RIS as well as the structures and processes for effective and appropriate RIS3 governance. This work has led to the development of a “tool box” to support RIS3 implementation. This toolbox is currently being developed and further refined and developed for application in less favoured regions across the EU.