More than 50% of global wetland area has been lost over the last 200 years, resulting in losses of habitat and species diversity as well as decreased hydrologic and biogeochemical functionality. Recognition of the magnitude of wetland loss as well as the wide variety of ecosystem services provided by wetlands has in recent decades led to an increased focus on wetland restoration. Restoration activities, however, often proceed in an ad hoc manner, with a focus on maximizing the total restored area rather than on other spatial attributes of the wetland network, which are less well understood. In this study, we have addressed the question of how human activities have altered the size distribution and spatial organization of wetlands over the Prairie Pothole Region of the Des Moines Lobe using high-resolution LIDAR data. Our results show that as well as the generally accepted 90% loss of depressional wetland area, there has been a preferential loss of smaller wetlands, with a marked alteration of the historical power-law relationship observed between wetland size and frequency and a resulting homogenization of the wetland size distribution. In addition, our results show significant decreases in perimeter-to-area ratios, increased mean distances between wetlands, particularly between smaller wetlands, and a reduced likelihood that current wetlands will be located in upland areas. Such patterns of loss can lead to disproportionate losses of ecosystem services, as smaller wetlands with larger perimeter-to-area ratios have been found to provide higher rates of biogeochemical processing and groundwater recharge, while increased mean distances between wetlands hinder species migration and thus negatively impact biodiversity. These results suggest the need to gear restoration efforts toward understanding and recreating the size distribution and spatial organization of historical wetlands, rather than focusing primarily on an increase in overall area.