This chapter presents the theme, theoretical approaches and overview of the chapters in the book. The theme is the contribution of cities (their actors) to increased sustainability in social-technical systems, eventually by accelerating sustainability improvements. The selected systems are energy, transport and healthcare. Cities may act as the cradle of key inventions, as places of up-scaling and commercialization and as places of quick adoption, though few individual cities take up all these roles. Next, several urban innovation theories are introduced, including agglomeration and cluster theories, and the relational (collaboration) approach, with the aim to ‘position’ the chapters. Specific attention is given to the entrepreneurial ecosystem approach. Complementary approaches are institutional and governance perspectives, in particular with respect to cities acting as institutional innovators. A final approach is the evolutionary approach, as invention, up-scaling, commercialization and adoption of new technology are concerned with long time-lines and manifold uncertainties.