The world's second largest zone of coastal hypoxia (oxygen depleted waters usually without marine organisms) is on the northern Gulf of Mexico continental shelf, adjacent to the outflows of the Mississippi and Atchafalaya Rivers. Decades of research, monitoring and retrospective analyses support the conclusion that land use in the watershed has changed significantly and is reflected in the ecology of the continental shelf. A paleo-reconstruction of continental shelf sediments confirms the significance of these water quality changes to coastal food webs, and suggests that the most recent influence on nutrient loading, from intense and widespread farming, has had a more significant effect than all previous landscape changes in the watershed. It is clear that nitrogen reductions in the sub-basins of the upper Midwest will be a key to the success of polices to reduce hypoxia, and scientists are playing a unique and important role in informing this policy process. The Action Plan developed by State, Federal and Tribal entitles identifies a quantitative goal for a reduced hypoxic zone -- a 30% reduction in the nitrogen load. The Plan recognizes that all nitrogen sources should be included in the strategy and includes other nutrients. However, because 74% of the nitrate load is from agricultural non-point sources, and because 56% of the total nitrate load comes from north of the Ohio River, it is clear that nitrogen reductions in the sub-basins of the upper Midwest will be a key to its implementation.