Conservation challenges enhance the need for quantitative information on dispersed bird populations in extensive landscapes, for techniques to monitor populations and assess environmental effects, and for conservation strategies at appropriate temporal and spatial scales. By estimating population sizes of shorebirds in the U.S. portion of the prairie pothole landscape in central North America, where most migrating shorebirds exhibit a highly dispersed spatial pattern, we determined that the region may play a vital role in the conservation of shorebirds. During northward and southward migration, 7.3 million shorebirds (95% CI: 4.3–10.3 million) and 3.9 million shorebirds (95% CI: 1.7–6.0 million) stopped to rest and refuel in the study area; inclusion of locally breeding species increases the estimates by 0.1 million and 0.07 million shorebirds, respectively. Seven species of calidridine sandpipers, including Semipalmated Sandpipers (Calidris pusilla), White-rumped Sandpipers (C. fuscicollis), and Stilt Sandpipers (C. himantopus), constituted 50% of northbound migrants in our study area. We present an approach to population estimation and monitoring, based on stratified random selection of townships as sample units, that is well suited to 11 migratory shorebird species. For extensive and dynamic wetland systems, we strongly caution against a monitoring program based solely on repeated counts of known stopover sites with historically high numbers of shorebirds. We recommend refinements in methodology to address sample-size requirements and potential sources of bias so that our approach may form the basis of a rigorous migration monitoring program in this and other prairie wetland regions.