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Targeted conservation approaches seek to focus resources on areas where they can deliver the greatest benefits and are recognized as key to reducing nonpoint source nutrients from agricultural landscapes into sensitive receiving waters. Moreover, there is growing recognition of the importance and complementarity of in-field and edge-of-field conservation for reaching nutrient reduction goals. Here we provide a generic prioritization that can help with spatial targeting and applied it across the conterminous US (CONUS). The prioritization begins with identifying areas with high agricultural nutrient surplus, i.e., where the most nitrogen (N) and/or phosphorus (P) inputs are left on the landscape after crop harvest. Subwatersheds with high surplus included 52% and 50% of CONUS subwatersheds for N and P, respectively, and were located predominantly in the Midwest for N, in the South for P, and in California for both N and P. Then we identified the most suitable conservation strategies using a hierarchy of metrics including nutrient use efficiency (proportion of new nutrient inputs removed by crop harvest), tile drainage, existing buffers for agricultural run-off, and wetland restoration potential. In-field nutrient input reduction emerged as a priority because nutrient use efficiency fell below a high but achievable goal of 0.7 (30% of nutrients applied are not utilized) in 45% and 44% of CONUS subwatersheds for N and P, respectively. In many parts of the southern and western US, in-field conservation (i.e., reducing inputs + preventing nutrients from leaving fields) alone was likely the optimal strategy as agriculture was already well-buffered. However, stacking in-field conservation with additional edge-of-field buffering would be important to conservation strategies in 35% and 29% of CONUS subwatersheds for N and P, respectively. Nutrient use efficiencies were often high enough in the Midwest that proposed strategies focused more on preventing nutrients from leaving fields, managing tile effluent, and buffering agricultural fields. Almost all major river basins would benefit from a variety of nutrient reduction conservation strategies, underscoring the potential of targeted approaches to help limit excess nutrients in surface and ground waters. • Overlaying surplus with conservation opportunities provides novel prioritization. • Nutrient use efficiency can guide conservation strategies. • Reducing in-field N and P inputs was the priority in ∼44% of US subwatersheds. • Stacking in-field and edge-of-field conservation in ∼30–35% of US subwatersheds. [ABSTRACT FROM AUTHOR]