Enhanced focus on population health is increasingly invoked as a potential solution to the persistent problems facing the US health care system including failures to achieve targets for health outcomes, eliminate disparities in health and health care, and function within a sustainable budget. Shortell1 recently discussed how the Affordable Care Act (ACA) and related developments could change incentives to align health care, public health, and social services. Sox2 further specified the inherent tensions in allocation of resources to balance the needs of individuals and those of the population overall and highlighted new aspects of medical professionalism that will be needed to improve population health outcomes. However, additional clarity is needed regarding the specific health system–based activities that may contribute most to improvements in population health and well-being and the barriers that must be overcome for them to succeed. These include stakeholder interests that may not be aligned with investments in population health, barriers to information transfer and service integration between health care and other sectors, and persistent difficulties in addressing health care disparities. Without solutions to these challenges, integration of population health–focused activities into the routine work of health care systems will be neither robust nor sustainable.