Since first diagnosed in the early 1990s, chronic kidney disease of unknown etiology (CKDu) has markedly increased in the North Central Province in the dry zone of Sri Lanka. CKDu has been identified as a global health issue in more than a dozen countries in Asia, South America, and the Middle East. It has been reported that out of these countries, Sri Lanka is the most affected, with the highest cases of CKDu patients and mortality rates. In Sri Lanka, the disease primarily affects male paddy (rice) farmers from low socioeconomic levels. A major river diversion scheme completed in the 70s feeds water from wet zones to ancient tanks that rely on rainwater only. The drinking water for the CKDu affected farming communities comes from the irrigation canals, shallow regolith water table aquifers recharged by canal seepage and precipitation, and deep-bored wells. Many contributing factors and hypotheses have been presented and discussed in the literature. Out of these multiple factors, the suspected environmental exposure pathways are through water (potable water and food) and air (unprotected pesticide spraying). Extensive data on water quality have been collected to develop, test, and support hypotheses on the role of water on the disease. However, no systematic investigations have been conducted to identify, study and analyze how pathways develop through the water storage and distribution systems from sources to the receptors where human exposure occurs. This study proposes a systems-based framework to conduct such analysis using numerical models of the intergraded surface and subsurface system. The models will simulate the fate and transport of naturally occurring toxins and agrichemicals and their geo-bio-chemicals transformation products. These models should incorporate characterization parameters of the surface water storage and distribution system and hydrogeologic data for shallow and deep aquifers, water quality data, epidemiological data, and climate drivers. Innovations methods to use the downscaled climate and regional hydrological model simulations to evaluate exposure pathways at local scales (e.g., villages) under different climate scenarios.