The pollution of water and food through human waste and anthropogenic activities, including industrial waste and agricultural runoff, is a mounting problem worldwide. Water pollution from microbes causes identifiable diarrhoeal illnesses. The consumption of water contaminated with heavy metals, fluoride, and other toxins causes insidious illnesses that lead to protracted, non-communicable diseases and death. Chronic kidney disease of unusual/uncertain/unknown aetiology is one such example, began to manifest in the mid-1960s in several dry-zonal agricultural societies in developing economies that are located around the equator. In Sri Lanka, such a disease is affecting the North Central Province, the rice bowl of the country that first appeared in the mid-1990s. Several potential causes have been postulated, including heavy metals, fluoride, cyanobacterial and algae toxins, agrochemicals, and high salinity and ionicity in water, but no specific source or causative factor has been identified for CKD of multifactorial origin (CKDmfo). Three large studies conducted in the recent past failed to find any of the postulated components (heavy metals, cyanobacterial toxins, fluoride, salinity, or agrochemicals) at levels higher than those deemed safe by the World Health Organization and the US Environmental Protection Agency. At the reported low levels in water and with the heterogeneous geographical distribution, it is unrealistic to expect any of these components individually could cause this disease. However, the additive or synergistic effects of a combination of factors and components, even at lower exposure levels, together with malnutrition and harmful behaviours, and/or a yet-unidentified (or not investigated) toxin, can cause this epidemic. Because the cause is unknown, scientists need to work on broader hypotheses, so that key causative elements are not missed. Taken together the plausibility of multiple factors in the genesis of this disease, the appropriate terminology is CKDmfo, a name that also indicates the need for multi-disciplinary research programs to facilitate identifying the cause(s) and the need for multiple approaches to eradicate it. While some potential causes remain to be investigated, existing data point to polluted water as the main source of this disease. This article evaluates pros and cons of each hypothesis and highlights the importance of among others, providing clean water to all affected and surrounding communities. Available data do not support any of the postulated agents, chemicals, heavy metals, fluoride, salinity/ionicity, or individual agrochemical components, such as phosphate or glyphosate, as causative factors for CKDmfo in Sri Lanka. However, as the CKDmfo name implies, a combination of these factors (or an unknown toxin) together with harmful behaviour and chronic dehydration may cause this disease. Irrespective of the cause, prevention is the only way forward for eradication.