The Gulf of Mexico hypoxic zone that was measured in July of 2013 was 15 120 km2, the result of riverine losses of nitrate and total P from the Mississippi River Basin (MRB). Despite twelve years of an action plan calling for reducing the zone to a five-year running average of 5000 km2 by 2015, little progress has been made (ref 1, Figure 1). To meet the hypoxic zone target, the 2007 plan called for 45% reductions in total N and total P. (2) There is no evidence that nutrient loading to the Gulf has decreased during this period. Here we discuss the biophysical and social barriers that have limited measurable progress. We suggest that the most viable approach to developing the suite of practices needed to reduce nutrient losses from agricultural fields is a partnership of researchers working closely with farmers to develop realistic practices on real-world farms (where the constraints that influence management are present), to document the effectiveness, and to communicate the environmental and socioeconomic results regionally. To widely implement the resulting nutrient reduction practices will require substantial new funding if we are to continue using our current agronomic production systems in the MRB.