As American colleges and universities have increasingly become involved in economic development since the mid-1980s, there has been a concomitant growth of interest in measuring the impacts of higher education on regional economies. This study examines the influences of 4-year colleges and universities in the United States at the metropolitan level, focusing on the internal and external factors that affect the generation of regional economic development impacts, the spatial extent of the impacts, and separating the effects of different university functions. Knowledge-based university activities, particularly teaching and basic research, are found to have substantial positive effects on regional earnings gains. The greatest impacts occur in small- and medium-sized regions, suggesting that universities may be able to act as a substitute for agglomeration economies. Spatial spillovers across regions are influential as well, indicating a relatively flat spatial gradient of university impacts that stretches to neighboring regions.