We synthesize and update the science supporting the Action Plan for Reducing, Mitigating, and Controlling Hypoxia in the Northern Gulf of Mexico (Mississippi River/Gulf of Mexico Watershed Nutrient Task Force 2001) with a focus on the spatial and temporal discharge and patterns of nutrient and organic carbon delivery to the northern Gulf of Mexico, including data through 2006. The discharge of the Mississippi River watershed over 200 years varies but is not demonstrably increasing or decreasing. About 30% of the Mississippi River was shunted westward to form the Atchafalaya River, which redistributed water and nutrient loads on the shelf. Data on nitrogen concentrations from the early 1900s demonstrate that the seasonal and annual concentrations in the lower river have increased considerably since then, including a higher spring loading, following the increase in fertilizer applications after World WarII. The loading of total nitrogen (TN) fell from 1990 to 2006, but the loading of total phosphorus (TP) has risen slightly, resulting in a decline in the TN:TP ratios. The present TN:TP ratios hover around an average indicative of potential nitrogen limitation on phytoplankton growth, or balanced growth limitation, but not phosphorus limitation. The dissolved nitrogen:dissolved silicate ratios are near the Redfield ratio indicative of growth limitations on diatoms. Although nutrient concentrations are relatively high compared to those in many other large rivers, the water quality in the Mississippi River is not unique in that nutrient loads can be described by a variety of land-use models. There is no net removal of nitrogen from water flowing through the Atchafalaya basin, but the concentrations of TP and suspended sediments are lower at the exit point (Morgan City, Louisiana) than in the water entering the Atchafalaya basin. The removal of nutrients entering offshore waters through diversion of river water into wetlands is presently less than 1% of the total loadings going directly offshore, and would be less than 8% if the 10,093 km² of coastal wetlands were successfully engineered for that purpose. Wetland loss is an insignificant contribution to the carbon loading offshore, compared to in situ marine production. The science-based conclusions in the Action Plan about nutrient loads and sources to the hypoxic zone off Louisiana are sustained by research and monitoring occurring in the subsequent 10 years.