The expected worldwide demand for agriculture, energy, and manufactured products will result in a supply chain that is increasingly dependent on exported rural products (e.g., livestock, cereal grains, fossil fuel, and biofuel). Rural areas such as the northern Great Plains are net exporters of food and energy, essentially “mining” valuable water and nutrient resources to do so. Rural areas are the foundation of supply chains; thus, to achieve sustainability, one must begin focusing at the source of the supply chain– with the farm, ranch, mine, or well. There are many knowledge gaps within the food–energy–water nexus in rural areas that shroud regional sustainability thresholds. Research and legislation are needed to address these critical issues.