The mission of American metropolitan universities has never before been so relevant, both to the future of institutions themselves and to the United States. The success of the mission requires that we develop a deep understanding of the impact of both urbanization and de-urbanization, as well as the challenges metropolitan universities face with accelerating globalization. It is the view of the authors that the present focus of metropolitan universities is inadequate for the challenges of the 21st century. A new approach is needed: one that regards the university as an enterprise, and which seeks to more cogently capitalize on existing strengths, identify new opportunities worldwide, support innovation, and ensure financial sustainability over the long haul. In short, metropolitan universities must adopt an approach that is global, enterprise-wide, entrepreneurial, and focused on research excellence, curricular innovation, and economic fundamentals.