Unlocking Smart Specialisation explores how European regions can design better strategies to grow, innovate and adapt in a rapidly changing world. George Papamichail examines the evolution of smart specialisation from an academic concept to a cornerstone of EU regional development, highlighting why many regions still struggle to put it into practice. Papamichail introduces key ideas from innovation systems theory, institutional theory and endogenous growth, connecting them with real-world policy application. He presents both the promise and the pitfalls of regional development, emphasising how regions succeed when they build on their unique strengths, engage local people and institutions and create trust-based collaboration. Chapters cover emerging trends such as S3 2.0, green and digital transitions and mission-oriented innovation, arguing that lasting success depends on efficient multilevel governance and institutional quality. Drawing on global examples, Papamichail concludes that smart specialisation will cultivate greener, fairer and more resilient futures in regions that have effectively closed the implementation gap. This is a valuable resource for students and scholars of public policy, economics and regional studies. Its recommendations for governance reform, capacity building and stakeholder engagement are also highly relevant for policymakers and practitioners in EU institutions, international organisations and regional development agencies.