Between 1937 and 1995 a complex of more than 100 interdunal wetlands disappeared from Great Sand Dunes National Monument, Colorado. We investigated three hypotheses that could explain wetland disappearance: (1) dune movement during a severe drought in the 1950s buried the wetlands, (2) agriculture related ground water pumping lowered the regional water table, and (3) changes in local hydrologic processes led to wetland loss. We used regional stream flow records, ground water level measurements, natural stable isotope analyses, soil stratigraphy, buried seed banks, and ground water modeling to address these hypotheses. Hydrologic data and stable isotope analyses illustrated the interaction between Sand Creek, a nearby stream, and the unconfined aquifer in the area where wetlands occurred. When the intermittent Sand Creek flows, seepage through its bed creates a large ground water mound under the creek. The seasonal development and dispersion of this mound propagates pressure waves through the aquifer that influence ground water levels up to 2 km from Sand Creek. Our data suggest the primary factors contributing to wetland disappearance were recent climatic fluctuations and incision of the Sand Creek channel. Below average stream flow between 1950 and 1980 reduced the duration of Sand Creek flow across the dune complex, minimizing ground water mound development. Consequently, the water table in the unconfined aquifer dropped ∼1.0 m and interdunal wetlands dried up. Twentieth Century incision of Sand Creek's channel reduced ground water mound height ∼2.5 m, decreasing seasonal water table fluctuations at interdunal wetlands and contributing to the overall water table decline. Long-term wet and dry cycles affect the water table elevation more than channel incision, leading us to conclude that many interdunal wetlands are ephemeral features. Wetland area is maximized during consecutive years of above average Sand Creek discharge and minimized as the water table drops during dry periods.