The global burden of CKD is considerable and has risen dramatically over the past 20 years. Recently, CKD of unknown origin (CKDu), a form of CKD among rural agricultural communities has been reported worldwide. There is no strong evidence for a single cause of CKDu. Basically, it is a phenotypic environmentally acquired disease with a combination of occupational and social factors. Across all geographical regions, CKDu was most frequently associated with men, middle age, snake bite, infection, and exposure to agrochemicals, heavy metals, herbal drugs, heat stress, and dietary exposures. CKDu has emerged as a challenge in certain regions of the world as there is no acceptable global definition for CKDu. There is an urgent need for health promotion at individual and community levels for early screening of risk factors and timely management. It is also important to strengthen the health service networks for a better quality of life and patient safety as well as adequate financing. Further etiological and interventional research is needed to reduce preventable regional risk factors as well as to develop proactive and comprehensive approaches to prevent and treat the disease.