This study aims to contribute to the understanding of the revitalization projects of metropolitan areas and the evolution of ecosystems of innovation. Using a case method approach, this work explores four Brazilian urban revitalization cases and dives into the evolution of the 22@Barcelona innovation district and the San Francisco-Silicon Valley ecosystem. From these cases, several implications can be drawn. On the one hand, from an academic point of view, both the Quintuple Helix model and the Knowledge Based Urban Development (KBUD) theory are found to provide an appropriate framework to map the revitalization processes analysed. On the other hand, policy makers in urban revitalization can benefit from this work by learning the lessons from the cities reviewed. We believe such cases can inspire other cities that want to transform old industrial areas (brownfield transformation) into socially conscious, creative and knowledge-based economy hubs. This study suggests the adoption of a holistic perspective that brings together the triple helix agents—universities, industry and government—while considering the local specificities in the urban, economic, social, and governance dimensions. We do so by theorizing the evolution of Areas of Innovation (AOIs) from inception to maturity.