Holistic approaches are needed to investigate the capacity of current water resource operations and infrastructure to sustain water supply and critical ecosystem health under projected drought conditions. Drought vulnerability is complex, dynamic, and challenging to assess, requiring simultaneous consideration of changing water demand, use and management, hydrologic system response, and water quality. We are bringing together a community of scientists from the U.S. Geological Survey, National Center for Atmospheric Research, Department of Energy, and Cornell University to create an integrated human-hydro-terrestrial modeling framework, linking pre-existing models, that can explore and synthesize system response and vulnerability to drought in the Delaware River Basin (DRB). The DRB provides drinking water to over 15 million people in New York, New Jersey, Pennsylvania, and Delaware. Critical water management decisions within the system are coordinated through the Delaware River Basin Commission and must meet requirements set by prior litigation. New York City has rights to divert water from the upper basin for water supply but must manage reservoir releases to meet downstream flow and temperature targets. The Office of the Delaware River Master administers provisions of the Flexible Flow Management Program designed to manage reservoir releases to meet water supply demands, habitat, and specified downstream minimum flows to repel upstream movement of saltwater in the estuary that threatens Philadelphia public water supply and other infrastructure. The DRB weathered a major drought in the 1960s, but water resource managers do not know if current operations and water demands can be sustained during a future drought of comparable magnitude. The integrated human-hydro-terrestrial modeling framework will be used to identify water supply and ecosystem vulnerabilities to drought and will characterize system function and evolution during and after periods of drought stress. Models will be forced with consistent input data sets representing scenarios of past, present, and future conditions. The approaches used to unify and harmonize diverse data sets and open-source models will provide a roadmap for the broader community to replicate and extend to other water resource issues and regions.