The article discusses the impact of recent global challenges, including the COVID-19 pandemic and geopolitical tensions, on Global Value Chains (GVCs) and Regional Systems of Innovation. These events have led to significant changes in how innovation is organized and managed, prompting a reevaluation of global and local dynamics. The article highlights the potential for a phase of de-globalization, where GVCs are being restructured, potentially altering the geography of economic activity. It emphasizes the need for a critical appraisal of how key contextual parameters have changed and the potential outcomes of these shifts. The article also outlines pressing issues for debate among scholars, policymakers, and practitioners, and presents insights from the articles in the Special Issue. The current state of GVCs has been affected by the pandemic, leading to disruptions and a reevaluation of their effectiveness. There is a growing emphasis on technological sovereignty and the need for strategic nationalization of critical industries to reduce vulnerabilities. The article also discusses the role of regional innovation systems in shaping economic activity, highlighting the importance of local-global interactions. It notes the impact of technological advancements, such as Industry 4.0 and artificial intelligence, on the reorganization of the global economy. The article also explores the regional embeddedness of innovation, emphasizing the localized nature of knowledge creation and the role of regional systems in fostering innovation. It discusses the challenges posed by the pandemic, including the shift to remote work and its impact on innovation dynamics. The article highlights the importance of innovation as a multiscalar phenomenon, requiring a combination of local and global collaborations to drive superior innovation capabilities. The article concludes by emphasizing the need for a critical juncture in the evolution of GVCs and regional innovation systems, highlighting the importance of understanding the complex interactions between local and global factors. It underscores the need for a comprehensive approach to innovation policy that considers the interplay between GVCs and regional systems of innovation. The article also highlights the potential for leapfrogging opportunities in developing countries, allowing them to catch up with industry leaders through strategic investments and partnerships. The article concludes with a call for further research on the long-term effects of these changes on the geography of innovation.The article discusses the impact of recent global challenges, including the COVID-19 pandemic and geopolitical tensions, on Global Value Chains (GVCs) and Regional Systems of Innovation. These events have led to significant changes in how innovation is organized and managed, prompting a reevaluation of global and local dynamics. The article highlights the potential for a phase of de-globalization, where GVCs are being restructured, potentially altering the geography of economic activity. It emphasizes the need for a critical appraisal of how key contextual parameters have changed and the potential outcomes of these shifts. The article also outlines pressing issues for debate among scholars, policymakers, and practitioners, and presents insights from the articles in the Special Issue. The current state of GVCs has been affected by the pandemic, leading to disruptions and a reevaluation of their effectiveness. There is a growing emphasis on technological sovereignty and the need for strategic nationalization of critical industries to reduce vulnerabilities. The article also discusses the role of regional innovation systems in shaping economic activity, highlighting the importance of local-global interactions. It notes the impact of technological advancements, such as Industry 4.0 and artificial intelligence, on the reorganization of the global economy. The article also explores the regional embeddedness of innovation, emphasizing the localized nature of knowledge creation and the role of regional systems in fostering innovation. It discusses the challenges posed by the pandemic, including the shift to remote work and its impact on innovation dynamics. The article highlights the importance of innovation as a multiscalar phenomenon, requiring a combination of local and global collaborations to drive superior innovation capabilities. The article concludes by emphasizing the need for a critical juncture in the evolution of GVCs and regional innovation systems, highlighting the importance of understanding the complex interactions between local and global factors. It underscores the need for a comprehensive approach to innovation policy that considers the interplay between GVCs and regional systems of innovation. The article also highlights the potential for leapfrogging opportunities in developing countries, allowing them to catch up with industry leaders through strategic investments and partnerships. The article concludes with a call for further research on the long-term effects of these changes on the geography of innovation.