<p>Global water systems are under intensifying stress from climate variability, population growth, institutional fragmentation, and deteriorating infrastructure. This paper presents a structured framework addressing twenty of the most pressing water management challenges worldwide, categorized across four domains: irrigation, water supply, water quality, and water governance. For each challenge, it identifies key management issues, policy and research priorities, and regional relevance. Drawing on over 200 peer-reviewed sources as well as original hydro-economic modeling from North America’s Rio Grande Basin, the paper illustrates how institutional innovation—particularly interdistrict and intradistrict water trading—can significantly enhance economic efficiency and adaptive capacity under drought. The model results highlight the superior performance of water markets relative to proportional shortage-sharing rules, demonstrating considerable gains in farm income and resource-use efficiency. More broadly, this paper’s original contribution provides decision-support guidance for researchers, practitioners, and policymakers working at the intersection of hydrology, infrastructure, and governance. By integrating economic analysis with cross-sectoral and regional insights, the paper advances a practical roadmap for building more resilient, equitable, and sustainable water systems in an era of growing uncertainty. Addressing Global Water Challenges in 2025: An Integrated Framework for Research, Policy, and Resource Management.</p>