Human activity is rapidly transforming most of Earth's natural systems. How this transformation is impacting human health, whose health is at greatest risk, and the magnitude of the associated disease burden are relatively new subjects within the field of environmental health. We discuss what is known about the human health implications of changes in the structure and function of natural systems and propose that these changes are affecting human health in a variety of important ways. We identify several gaps and limitations in the research that has been done to date and propose a more systematic and comprehensive approach to applied research in this field. Such efforts could lead to a more robust understanding of the human health impacts of accelerating environmental change and inform decision making in the land-use planning, environmental conservation, and public health policy realms.At least since Hippocrates wrote On Airs, Waters, and Places, the natural environment has been viewed as an important determinant of human health. However, over the last century, the field of environmental health has focused increasingly on quantifying exposure-response relationships for toxins encountered in the human-dominated environment: from an initial focus on workplace exposures, to a population-level focus on radiation, heavy metals, air and water pollution, and more recently, to exposure to endocrinedisrupting chemicals. Over this period, relatively little attention has been paid to how changes in the structure and function of Earth's natural systems might affect human health. Growing evidence that changes in these natural systems can affect human health in a variety of important ways and the increasing pace and extent of these changes has prompted this Perspective. In it, we review current understanding of this field, identify some of its gaps and limitations, and suggest an approach to expanding our understanding.Human activity is transforming nearly all of Earth's natural systems. With the human population now exceeding 7 billion people and rapid growth in per capita consumption of goods and services, humanity's growing ecological footprint is altering the planet's land cover, rivers and oceans, climate system, biogeochemical cycles, and the