A new modeling effort exploring the opportunities, constraints, and interactions between mitigation and adaptation at regional scale is utilizing stakeholder engagement in an innovative approach to guide model development and demonstration, including uncertainty characterization, to effectively inform regional decision making. This project, the integrated Regional Earth System Model (iRESM), employs structured stakeholder interactions and literature reviews to identify the most relevant adaptation and mitigation alternatives and decision criteria for each regional application of the framework. The information is used to identify important model capabilities and to provide a focus for numerical experiments. This paper presents the stakeholder research results from the first iRESM pilot region. The pilot region includes the Great Lakes Basin in the Midwest portion of the United States as well as other contiguous states. This geographic area (14 states in total) permits cohesive modeling of hydrologic systems while also providing strong gradients in climate, demography, land cover/land use, and energy supply and demand. The results from the stakeholder research indicate that, for this region, iRESM should prioritize addressing adaptation alternatives in the water resources, urban infrastructure, and agriculture sectors, including water conservation, expanded water quality monitoring, altered reservoir releases, lowered water intakes, urban infrastructure upgrades, increased electric power reserves in urban areas, and land use management/crop selection changes. For mitigation in this region, the stakeholder research implies that iRESM should focus on policies affecting the penetration of renewable energy technologies, and the costs and effectiveness of energy efficiency, bioenergy production, wind energy, and carbon capture and sequestration.