During the last two decades, Sri Lanka, located close to the equator, has experienced an escalating incidence of chronic kidney disease (CKD) of unknown aetiology (CKDue) in dry zonal areas. Similar incidences of unusual CKDs have been reported in the dry zonal, agricultural areas of several other equatorial countries. In Sri Lanka, the incidence of CKDue is highest in the North Central Province (NCP), where approximately 45 % of the country's paddy fields are located. However, in recent years, the disease has spread into areas adjacent to as well as distant from the NCP. The cause of CKD in Sri Lanka is unknown, and may likely due to interactions of different potential agents; thus, CKD is of multi-factorial origin (CKD-mfo). These factors include, the negative effects from overuse of agrochemicals. Nevertheless, the potential interactions and synergism between probable agents have not been studied. This systematic review discusses the proposed hypotheses and causes of CKD-mfo in Sri Lanka, and ways to decrease the incidence of this disease and to eradicate it, and provide some recommendations. During the past decade, a number of groups have investigated this disorder using different methodologies and reported various correlations, but failed to find a cause. Research has focussed on the contamination of water with heavy metals, agrochemicals, hard water, algae, ionicity, climate change, and so forth. Nevertheless, the levels of any of the pollutants or conditions reported in water in NPC are inconsistent not correlated with the prevalence of the disease, and are too low to be the sole cause of CKD-mfo. Meanwhile, several nephrotoxins prevalent in the region, including medications, leptospirosis, toxic herbs, illicit alcohol, locally grown tobacco, and petrochemicals, as well as the effects of changed habits occured over the past four decades have not been studied to date. Taken together, the geographical distribution and overall findings indicate that combinations of factors and/or their interactions are likely to precipitate CKD-mfo, which kills more than 5,000 people annually in Sri Lanka; most victims are middle-aged male farmers. Much anecdotal evidence from this region suggests that consumption of contaminated water is the most likely source of this deadly disease. Although the aetiology is unknown, prevention of this "environmentally acquired" disease seems relatively straightforward. Solutions include (a) preventing environmental pollution, (b) stopping the irresponsible use and decreasing the usage of agrochemicals, and encouraging the use of environmentally friendly agricultural methods, (c) taking proper precautions when using agrochemicals and safe disposal of their containers, (d) changing the risky behaviour of farmers and educating them to preserve the environment, and (e) providing clean potable water to all affected regions. Implementing a well-coordinated, in-depth, region-wide, broad-based research study together with a long-term effective surveillance programme across the country is essential to curbing this disease. Unless firm actions are taken promptly, more than three million healthy people in the country, live in agricultural regions, are at risk for contracting CKD-mfo and succumb to premature deaths, which are preventable.