We discuss the sustainability of natural and human systems in the United States in relation to 21st century threats associated with energy scarcity, climate change, the loss of ecosystem services, the limitations of neoclassical economics, and human settlement patterns. Increasing scarcity and the decreasing return on investment for existing conventional energy reserves are expected to significantly reduce the amount of affordable energy for societal needs and demands. This will also make dealing with the predicted impacts of climate change more difficult and expensive. Climate change will threaten the present sustainability of natural environments, agriculture, and urban areas but these impacts will manifest themselves differentially across the landscape. The impacts of projected climate change will make living in arid regions of the southern Great Plains, the Southwest, and the southern half of California increasingly difficult. Accelerated sea-level rise and increased frequency of strong hurricanes will increase the vulnerability of natural and human systems along the Gulf and Atlantic coasts while making them less sustainable. Ecosystem services provided by natural environments form the basis for the human economy everywhere and are also at risk from climate change impacts and overuse. Decreasing energy availability, climate change, and continued degradation of ecosystem services are likely to make continued economic growth difficult if not impossible. The capacity of neoclassical economics to effectively deal with these growing threats is limited. The areas of the country most compromised by these 21st century trends are likely to be the southern Great Plains, Southwest, southern California, the Atlantic and Gulf coasts, and densely populated areas everywhere, but especially in the northeast, Midwest, and southern California.