Concentrated animal feeding operations (CAFOs) are very large feeding businesses that are purposely designed to highly pollute. They have developed in the American South and Great Plains. They are designed to spread manure effluent into the tributaries of America’s most significant rivers, and ultimately into its main arteries such as the Mississippi and Missouri Rivers. This effluent is the direct cause of the “dead zone,” a large area of algae blooms that appears every summer in the Gulf of Mexico. Through ineffective supervision, the states of these regions have purposely allowed this effluent pollution to flow to neighboring downstream states. Here, the solution is for the US EPA to regulate this larger regional problem. The Waterkeepers (formerly the Riverkeepers) have been litigating this problem to establish the regional regulation through its “Pure Farms, Pure Waters” campaign. This attempt to develop effective regional regulation of this “tragedy of the commons” is reviewed in this chapter. This sort of regional regulation was previously and successfully established for the Chesapeake Bay through the efforts of the Chesapeake Bay Foundation working with the EPA.