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This thesis identifies and discusses persistent challenges limiting the success of current waterborne disease management strategies and several existing research hurdles that continue to impede characterization of microbial transmission and transport. In this work, the Chobe River watershed in Northern Botswana serves as a target study site for the application of hydrological modeling tools to quantify emergent water quality and health challenges in Southern Africa. A watershed model with extensive data requirements, the Hydrological Simulation Program – Fortran (HSPF), is used to identify primary data gaps and model assumptions that limit the progress of model development, and guide opportunities for data collection, tool development, and research direction. Environmental pathogen exposure risk and epidemiological outbreak dynamics are best described by interactions between the coupled human and environmental processes within a system. 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In this work, the Chobe River watershed in Northern Botswana serves as a target study site for the application of hydrological modeling tools to quantify emergent water quality and health challenges in Southern Africa. A watershed model with extensive data requirements, the Hydrological Simulation Program – Fortran (HSPF), is used to identify primary data gaps and model assumptions that limit the progress of model development, and guide opportunities for data collection, tool development, and research direction. Environmental pathogen exposure risk and epidemiological outbreak dynamics are best described by interactions between the coupled human and environmental processes within a system. 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