This report analyzes the start-up ecosystem in Tokyo and the greater surrounding area in Japan in the transition of the innovation model to a hybrid of traditional public sector-university-corporation research and development (R&D) combined with start-up agile innovation. It first introduces the role of a start-up ecosystem in contributing to the development of global cities, and thus to the wider national economy. It then takes a country-level view of Japan’s innovation system, within which the metropolitan region operates, in the transition to the innovation-start-up ecosystem. This description is followed by an analysis of the specifics of the Tokyo start-up ecosystem—which consists of investment, support infrastructure, and skills infrastructure—factors that merit close inspection and deep analytics. And finally, the report ends with conclusions—what could be done better or differently to exploit opportunities within Tokyo—but also wider lessons for other global cities. This report is intended to address a gap in the analysis of Tokyo’s start-up ecosystem and its comparison with other leading global start-up ecosystems. Its main goals are to shine light into the opportunities to increase the ecosystem’s performance and influence as a global innovation hub and to show the lessons learned from Tokyo’s experience.