Sustainable management of aquatic ecosystems is a worldwide priority; the integrity of these systems depends, in turn, on the integrity of the watersheds (catchments) in which they are embedded. In this article, we present the concepts, background, and scientific foundations for assessing, both nationally and at finer scales, the relationships between ecosystem services, human health, and socioeconomic values in the context of water quality, water quantity, landscapes, the condition of watersheds, and the connectivity of waters, from headwaters to estuaries and the coastal ocean. These assessments will be a foundation for what we have termed â€Owatershed epidemiology,” through which the connections between ecosystems and human health can be explored over broad spatial and temporal scales. Understanding and communicating these relationships should lead to greater awareness of the roles watersheds play in human well-being, and hence to better management and stewardship of water resources. The U.S. Environmental Protection Agency is developing the research, models, and planning tools to support operational national assessments of watershed sustainability, building upon ongoing assessments of aquatic resources in streams, rivers, lakes, wetlands and estuaries.