The contamination of food and water through waste and agricultural runoff poses serious threats to humans. Pollution with microbes causes noticeable diarrheal diseases, whereas agrochemicals, heavy metals, fluoride, and toxins cause insidious diseases and premature deaths. Chronic kidney disease of unknown origin (CKDuo) was first seen in dry-zonal agricultural regions in equatorial countries in the mid-1960s, and in Sri Lanka, in mid-1990s. A number of agents and toxins have been postulated as the cause of CKD of multifactorial origin (CKDmfo/CKDuo), including heavy metals, agrochemicals, fluoride, fungal and bacterial toxins, climate change; and a number of behavioral factors. Meanwhile, several other potential nephrotoxic causes have not been investigated, including the indiscriminate and excessive use of non-steroidal antiinflammatory drugs, illegal drugs and illicit alcohol, microbial agents (leptospirosis, Hanta virus etc.), chronic dehydration, and exposure to various combinations of these toxic agents in the presence of unhealthy habits. The incidence of CKDmfo is doubling every 4 to 5 years in Sri Lanka, leading to more than 5,000 deaths annually; excess of 150,000 people are currently affected. Although a number of agents have been postulated, no single offending agent has been identified as the cause of CKDmfo. To alleviate CKDmfo, it is essential to take a broader, holistic approach: carry out a massive awareness campaign, prevent environmental pollution, lessen malnutrition, correct unhealthy behaviors and habits acquired during recent past, and provide clean water completely devoid of nephrotoxins to all inhabitants in the affected communities. A sustained, coordinated, targeted, and effective approach is essential to decrease the disease incidence, prevention of premature deaths, and eradication of CKDmfo. This review explores pros and cons of agrochemicals as a potential cause of this deadly disease.