In this paper, we analyze how the physical layout of cities affects innovation by influencing the organization of knowledge exchange. We exploit a novel data set covering all census block groups in the contiguous United States with information on innovation outcomes, street infrastructure, as well as population and workforce characteristics. To deal with concerns of omitted variable bias, we apply commuting zone fixed effects and construct instruments based on historic city planning. The results suggest that variation in street network density may explain regional innovation differentials beyond the traditional location externalities found in the literature.