In the face of future climate change, it is prudent to seek sustainable adaptation strategies to address regional and local impacts. These impacts are multidimensional, involving interdependencies between systems (weather, urban land use, agriculture, etc.) that are typically modeled independently. To achieve a holistic understanding and thus identify more effective strategies for addressing and/or mitigating impacts, an integrated interdisciplinary research approach is essential. Here we discuss the broader challenges and threats faced by regions encompassing large bodies of water. We illustrate with North America's Great Lakes region, discussing how an integrated model of atmosphere, land, and lake could provide critical information to inform decisions. We stress the need to include input from diverse stakeholders in the development of tools to ensure the quality and usability of impact assessments. Research investments toward such capabilities should engage multiple disciplines including atmospheric sciences, hydrodynamics, hydrology, and biogeochemistry as well as data analytics and modeling. Also, detailed measurement and documentation of urban and agricultural land use, lake surface temperature and ice‐cover, and observations of energy and mass exchanges at the interfaces of atmosphere, land, and water are needed. We envision the development of an integrated set of modeling tools that will improve both the utility of weather forecasts and long‐term climate projections of the impacts on ecosystem sustainability, hydrometeorological extremes, engineering design, human health, and socioeconomic systems. Such a modeling system can serve as a template for other regions with cities, large lakes, inland seas, and coastlines facing similar kinds of climate change impacts.