As economies in the European Union Enlargement and Neighbourhood Region are gathering pace in developing their respective Smart Specialisation Strategies, their focus is moving from the design to the implementation phase. This has generated a need for a structured implementation framework, that is easy to follow and provides full descriptions of roles and responsibilities, as well as organisational and management needs for each sub-stage of implementation. Analogous to the S3 framework that provided the structure for completing stages in the Smart Specialisation design phase, which has proven highly efficient for Smart Specialisation in the EU Enlargement and Neighbourhood Region, this guidebook introduces the architecture for the implementation of Smart Specialisation actions. The proposed S3 implementation framework gives a detailed overview of each activity, organising them into segments with extensive information on requirements and needs for every stage of the process.