The Prairie Pothole Region (PPR) contains ecosystems that are typified by an extensive matrix of grasslands and depressional wetlands, which provide numerous ecosystem services. Over the past 150 years the PPR has experienced numerous landscape modifications resulting in agricultural conversion of 75–99 % of native prairie uplands and drainage of 50–90 % of wetlands. There is concern over how and where conservation dollars should be spent within the PPR to protect and restore wetland basins to support waterbird populations that will be robust to a changing climate. However, while hydrological impacts of landscape modifications appear substantial, they are still poorly understood. Previous modeling efforts addressing impacts of climate change on PPR wetlands have yet to fully incorporate interacting or potentially overshadowing impacts of landscape modification. We outlined several information needs for building more informative models to predict climate change effects on PPR wetlands. We reviewed how landscape modification influences wetland hydrology and present a conceptual model to describe how modified wetlands might respond to climate variability. We note that current climate projections do not incorporate cyclical variability in climate between wet and dry periods even though such dynamics have shaped the hydrology and ecology of PPR wetlands. We conclude that there are at least three prerequisite steps to making meaningful predictions about effects of climate change on PPR wetlands. Those evident to us are: 1) an understanding of how physical and watershed characteristics of wetland basins of similar hydroperiods vary across temperature and moisture gradients; 2) a mechanistic understanding of how wetlands respond to climate across a gradient of anthropogenic modifications; and 3) improved climate projections for the PPR that can meaningfully represent potential changes in climate variability including intensity and duration of wet and dry periods. Once these issues are addressed, we contend that modeling efforts will better inform and quantify ecosystem services provided by wetlands to meet needs of waterbird conservation and broader societal interests such as flood control and water quality.