The article discusses the interplay between Global Value Chains (GVCs) and Regional Systems of Innovation in the context of recent global challenges, including the COVID-19 pandemic and geopolitical tensions. It highlights how these events have impacted both GVCs and Regional Systems of Innovation, leading to a potential phase of de-globalization and restructuring of economic activity. The article outlines pressing issues for scholars, policymakers, and practitioners, and introduces a set of articles that explore the current challenges and potential outcomes of these shifts. It emphasizes the importance of understanding how countries, regions, firms, and individuals will respond to multifaceted crises and productive rearrangements, and the implications for innovation and economic resilience. The article also discusses the role of technological sovereignty, the impact of Industry 4.0 and artificial intelligence, and the potential for leapfrogging opportunities in developing regions. Finally, it provides an overview of the major findings from the special issue, which includes micro-oriented and macro-oriented perspectives on the challenges and opportunities in the interplay between GVCs and Regional Systems of Innovation.The article discusses the interplay between Global Value Chains (GVCs) and Regional Systems of Innovation in the context of recent global challenges, including the COVID-19 pandemic and geopolitical tensions. It highlights how these events have impacted both GVCs and Regional Systems of Innovation, leading to a potential phase of de-globalization and restructuring of economic activity. The article outlines pressing issues for scholars, policymakers, and practitioners, and introduces a set of articles that explore the current challenges and potential outcomes of these shifts. It emphasizes the importance of understanding how countries, regions, firms, and individuals will respond to multifaceted crises and productive rearrangements, and the implications for innovation and economic resilience. The article also discusses the role of technological sovereignty, the impact of Industry 4.0 and artificial intelligence, and the potential for leapfrogging opportunities in developing regions. Finally, it provides an overview of the major findings from the special issue, which includes micro-oriented and macro-oriented perspectives on the challenges and opportunities in the interplay between GVCs and Regional Systems of Innovation.