This paper seeks to put cities and regions at the very center of the processes of innovation and entrepreneurship. To do so, we marry the insights of Jane Jacobs and more urban and regional thinking and research on the role of the city and the region to the literature on innovation and entrepreneurship going back to Joseph Schumpeter. Theory and research on innovation and entrepreneurship and their geography privileges the firm, industry clusters and/or the individual and poses the city as a container for them. Jacobs famously theorized that it is the city that is the key organizing unit for innovation, entrepreneurship, and economic growth. Marrying Jacobs’ insights on cities to those of Schumpeter on innovation, we argue that innovation and entrepreneurship do not simply take in place in cities but in fact require them.