As the US begins to integrate biomass crops and residues into its mix of energy feedstocks, tools are needed to measure the long-term sustainability of these feedstocks. Two aspects of sustainability are long-term potential for profitably producing energy and protection of ecosystems influenced by energy-related activities. The Soil and Water Assessment Tool (SWAT) is an important model used in our efforts to quantify both aspects. To quantify potential feedstock production, we used SWAT to estimate switchgrass yields at a national scale. The results from this analysis produced a map of the potential switchgrass yield along its natural eastern range. To quantify ecological protection, we are using the SWAT model to forecast changes in water quality and fish richness as result of landscape alterations due to incorporating bioenergy crops. We have implemented the SWAT model in the Arkansas-Red-White region, which drains into the Mississippi River, and we present our methods here. We identified two sub-watershed for sensitivity analysis and calibration of the water quality results, and then, explored ways to apply the calibration results to the whole region and validate the model setup. We also present an overview of our research in which results from the calibrated regional SWAT model were used to analyze potential changes in fish biodiversity. Only by evaluating the energy and environmental implications of landscape changes can we make informed decisions about bioenergy at the national scale, and the SWAT model will enable us to reach that goal.