Although running water is the dominant geomorphic agent on Earth, eolian processes can gain ascendancy in regions where the climate is arid, vegetation is sparse, and abundant sand is available for transport. With climate change, the boundaries between fluvial-dominated and eolian-dominated areas may shift. Although there have been few reports in the North American literature of river systems blocked by dune sand, our work in the Nebraska Sand Hills provides evidence of multiple episodes of such blockage events. During prolonged arid intervals in latest Pleistocene and middle Holocene time, eolian dune sand blocked two large valley systems in western Nebraska. These blockages raised the water table of the High Plains aquifer as much as 25 m over an area of 7000 km2 and created over one thousand lakes. Wetlands far removed from the discharge points of the buried paleovalley system are strongly alkaline (exceeding 250 000 mg/L total dissolved solids [TDS]). Relatively fresh (280 mg/L TDS), flow-through lakes are present at the distal end of the system where the gradient of the water table is steep and the cross section of the buried valley is large. Anomalously thick marsh and lake sediments accumulated in deep paleovalleys upstream of dune dams near the southern margin of the Sand Hills. Our cores and radiocarbon dates from Blue and Crescent Lakes reveal their histories to be quite distinct from adjacent Swan Lake; these differences are best explained by multiple blockage events. Our work explains why lakes are most abundant in the driest part of the Sand Hills. It also provides another line of evidence for major dune activity in the Sand Hills region during Holocene time and shows that factors other than regional climate, specifically location, height, and hydraulic conductivity of dune dams, can control the rise and fall of the ground-water table and the chemistry of lakes.