The United States and European Union differ significantly in terms of their innovative capacity: the former have been able to gain and maintain world leadership in innovation and technology while the latter continues to lag. Notwithstanding the magnitude of this innovation gap and the political emphasis placed upon it on both sides of the Atlantic, very little systematic comparative analysis has been carried out on its causes. The empirical literature has emphasized the structural differences between the two continents in the quantity and quality of the major ‘inputs’ to innovation: R&D investments and human capital. The very different spatial organization of innovative activities in the EU and the US—as suggested by a variety of contributions in the field of economic geography—could also influence innovative output. This article analyses and compares a wide set of territorial processes that influence innovation in Europe and the United States. The higher mobility of capital, population and knowledge in the US not only promotes the agglomeration of research activity in specific areas of the country but also enables a variety of territorial mechanisms to fully exploit local innovative activities and (informational) synergies. In the European Union, in contrast, imperfect market integration and institutional and cultural barriers across the continent prevent innovative agents from maximizing the benefits from external economies and localized interactions, but compensatory forms of geographical process may be emerging in concert with further European integration.