Objective: Even when initially successful, many interventions aimed at reducing the toll of water-related infectious disease have not been sustainable over longer periods of time. Here we review historical practices in water-related infectious disease research and propose an interdisciplinary public health oriented systems approach to research and intervention design. Data sources: On the basis of the literature and the authorsÕ experiences, we summarize contributions from key disciplines and identify common problems and trends. Practices in developing countries, where the disease burden is the most severe, are emphasized. Data extraction: We define waterborne and water-associated vectorborne diseases and identify disciplinary themes and conceptual needs by drawing from ecologic, anthropologic, engineering, political/economic, and public health fields. A case study examines one of the classes of water-related infectious disease. Data synthesis: The limited success in designing sustainable interventions is attributable to factors that include the complexity and interactions among the social, ecologic, engineering, political/economic, and public health domains; incomplete data; a lack of relevant indicators; and most important, an inadequate understanding of the proximal and distal factors that cause water-related infectious disease. Fundamental change is needed for research on water-related infectious diseases, and we advocate a systems approach framework using an ongoing evidence-based health outcomes focus with an extended time horizon. The examples and case study in the review show many opportunities for interdisciplinary collaborations, data fusion techniques, and other advances. Conclusions: The proposed framework will facilitate research by addressing the complexity and divergent scales of problems and by engaging scientists in the disciplines needed to tackle these difficult problems. Such research can enhance the prevention and control of water-related infectious diseases in a manner that is sustainable and focused on public health outcomes.