Climate change continues to challenge food, energy, and water systems (FEWS) across the globe and will figure prominently in shaping future decisions on how best to manage this nexus. In turn, traditionally engineered and natural infrastructures jointly support and hence determine FEWS performance, their vulnerabilities, and their resilience in light of extreme climate events. We present here a research framework to advance the modeling, data integration, and assessment capabilities that support hypothesis-driven research on FEWS dynamics cast at the macro-regional scale.