Currently, USEPA is considering nutrient standards for nitrogen and phosphorus to decrease nutrient loads from the agricultural Midwest to the Gulf of Mexico as well as to protect against local eutrophication, especially during low flow periods. Designing a nutrient standard that protects against downstream loading during high flow periods and also preserves stream biotic integrity during low flow remains a challenge for EPA. We use data from 18 years of our research on Illinois watersheds to document conditions when the majority of nutrient losses occur and when water quality is impaired. Initially, chlorophyll-a in the water column was considered a possible nutrient standard criterion; however, our results show that a consistent cause and effect relationship between nutrient concentration and impairment (dissolved oxygen below 5 mg L^-1) is weak due to factors such as turbidity, canopy cover, and substrate. Our analyses of the Mississippi River Basin indicates that the largest contributing source of nitrate to the Gulf of Mexico is from extensively tile drained areas of the Midwest, and a large contributor of phosphorus is from sewage effluent. Although N fertilizer use has remained constant and P fertilizer use has declined during the past 30 years, we have not observed a decrease in nutrient runoff from fields to streams. Additionally, we found that removing P from sewage effluent (<0.5 mg L^-1) in an agriculturally dominated stream did not decrease stream P concentration below a critical minimum that would reduce eutrophication. In Illinois, agricultural runoff generally occurs in late winter and spring, while sewage effluent impacts are greatest during late summer and fall when agricultural contributions are negligible. Our results underscore the difficult challenge of creating nutrient standards that minimize eutrophication during low flow periods and decrease loads during high flow periods in a dominantly agricultural state, but one with a large population.