Every summer, a large area forms in the northern Gulf of Mexico where dissolved oxygen becomes too low for many aquatic species to survive. This “hypoxic zone” is fueled by nutrient (nitrogen and phosphorus) runoff from the Mississippi/Atchafalaya River Basin (MARB), most of which comes from agriculture. This analysis used the ERS Regional Environment and Agriculture Programming (REAP) model and data from the USDA Conservation Effects Assessment Project (CEAP) to assess the most cost-effective way of achieving a 45-percent reduction in cropland nutrient loads to the Gulf. Strategies involve adoption of management practices that reduce nutrient loss from fields to water resources, off-field practices for intercepting nutrients, retirement of marginal cropland, and other changes in crop management. Results suggest that proximity to the Gulf was a major factor in the location of nutrient-reduction efforts when reducing Gulf hypoxia was the only goal. When local as well as Gulf nutrient-reduction targets are applied, nutrient-reduction efforts are spread more evenly across the MARB. Adopting nutrient management practices, restoring wetlands, and retiring cropland to meet water quality goals also increased commodity prices, resulting in more intensive production outside the MARB and increased nutrient and sediment loadings to water in other watersheds.