This research aims to improve our knowledge of anthropogenic and natural impacts on water resources by evaluating and refining the science of predicting pollutant (nutrient and sediment) loadings from medium- to large-scale watersheds. To enable these goals, this research is centered on large watersheds in the Midwestern United States, which have been some of the primary sources of nutrient and sediment loadings to downstream water bodies such as the Gulf of Mexico and Lake Erie. In total, 14 watersheds in Illinois, Indiana, Ohio, and Michigan, with extensive water quality datasets, are analyzed in different stages of this research. Most of these watersheds are predominantly agricultural with intensive row-cropped farmlands and have a network of sub-surface tile drainage systems.