Optimizing the health of populations, whether defined as persons receiving care from a health care delivery system or more broadly as persons in a region, is emerging as a core focus in the era of health care reform. To achieve this goal requires an approach in which preventive care is valued and “nonmedical” determinants of patients’ health are engaged. For large, multimission systems such as academic medical centers, navigating the evolution to a population-oriented paradigm across the domains of patient care, education, and research poses real challenges but also offers tremendous opportunities, as important objectives across each mission begin to align with external trends and incentives. In clinical care, opportunities exist to improve capacity for assuming risk, optimize community benefit, and make innovative use of advances in health information technology. Education must equip the next generation of leaders to understand and address population-level goals in addition to patient-level needs. And the prospects for research to define strategies for measuring and optimizing the health of populations have never been stronger. A remarkable convergence of trends has created compelling opportunities for academic medical centers to advance their core goals by endorsing and committing to advancing the health of populations.