Changes in advanced manufacturing technologies as well as the economics of manufacturing have significant implications for the location and spatial organization of production. As firms employ advanced manufacturing technologies to create ‘smart’ and connected factories, engage in mass customization, further integrate R&D with manufacturing to enhance innovation, rethink their supply chains to shorten lead times, and demand higher skills and talent from a range of disciplines, where and how twenty-first century manufacturing occurs opens up in ways that have been largely inconceivable in the past. Countries and regions globally are investing heavily in advanced manufacturing technologies because of their important link to innovation and economic development more broadly. However, the implications of these trends for urban manufacturing are mixed and uneven. While manufacturing jobs continue to decline and strong market cities lose more industrial land to conversions to residential and tech offi ce use, greater access to manufacturing tools and technologies are reducing barriers to entry and a new generation of entrepreneurs, artisans and students are engaging in manufacturing and creating a range of new ‘maker spaces’ in cities. At the same time, the changing economics and emphasis on innovation are making manufacturing in cities and metropolitan areas more feasible for firms in regional industry clusters that rely on advanced manufacturing capabilities. Using a case study from the US state of Massachusetts, this paper proposes a new systems approach for thinking about urban manufacturing that blurs geographic boundaries and looks more closely at the manufacturing innovation ecosystem as a whole and how land-use strategies might support this system.