We present here and in the companion papers an analysis of sustainability in the Middle Rio Grande region of the U.S.-Mexico border and propose an interdisciplinary research agenda focused on the coupled human and natural dimensions of water resources sustainability in the face of climate and social change in an international border region. Key threats to water sustainability in the Middle Rio Grande River region include: (1) increasing salinization of surface and ground water, (2) increasing water demand from a growing population in the El Paso/Ciudad Juarez area on top of an already high base demand from irrigated agriculture, (3) water quality impacts from agricultural, municipal, and industrial discharges to the river, (4) changing regional climate that portends increased frequency and intensity of droughts interspersed with more intensive rainfall and flooding events, and (5) disparate water planning and management systems between different states in the U.S. and between the U.S. and Mexico. In addition to these challenges, there is an increasing demand from a significant regional population who is (and has been historically) underserved in terms of access to affordable potable water. To address these challenges to water resources sustainability, we have focused on: (1) the determinants of resilience and transformability in an ecological/social setting on an international border and how they can be measured and predicted; and (2) the drivers of change … what are they (climate, social, etc.) and how are they impacting the coupled human and natural dimensions of water sustainability on the border? To tackle these challenges, we propose a research agenda based on a complex systems approach that focuses on the linkages and feedbacks of the natural, built/managed, and social dimensions of the surface and groundwater budget of the region. The approach that we propose incorporates elements of systems analysis, complexity science, and the use of modeling tools such as scenario planning and back-casting to link the quantitative with the qualitative. This approach is unique for our region, as are our bi-national focus and our conceptualization of “water capital”. In particular, the concept of water capital provides the basis for a new interdisciplinary paradigm that integrates social, economic, and natural sectors within a systems framework in order to understand and characterize water resources sustainability. This proposed approach would not only provide a framework for water sustainability decision making for our bi-national region at the local, state, and federal levels, but could serve as a model for similar border regions and/or international rivers in arid and semi-arid regions in the Middle East, Africa, Asia, and Latin America.