Innovation districts are a relatively new strategy in urban economic development. They have been fast gaining attention and popularity, due in part to energetic third-party promotion and the apparent successes of two early adopters: Barcelona and Boston. As additional cities establish and promote innovation districts, it benefits policymakers to possess information regarding their characteristics and suitability as an economic development approach. We conduct in-depth case studies of four innovation districts in the United States—located in Boston, Detroit, Saint Louis, and San Diego—that present contrasting settings, policies, and outcomes. The empirical information is drawn primarily from interviews with the innovation district creators and implementers and the entrepreneurs embedded within them. We assess the expectations, design, implementation, and operation of these innovation districts, with reference to stated and normative policy goals along with theories of regional economic development. Our purpose is to provide scholars and policymakers with guidance as to how, and how well, innovation districts may achieve the aim of urban economic development to generate economic dynamism and prosperity.