Diabetic nephropathy (DN) is a chronic microvascular disease mainly secondary to diabetes. Its pathogenesis is affected by gene polymorphism, environmental factors, and so on. More and more studies have shown that epigenetic regulation mechanism without gene sequence changes plays an important role in occurrence and development of DN. The epigenetic regulation mechanism changes dynamically with the change of the surrounding environment. Transient environmental change, such as short-term high glucose, can lead to epigenetic regulation mechanism changes, affect histone exposed amino acid residue modification, DNA methylation level, etc., regulate the expression of related genes, and eventually promote the pathophysiological changes such as inflammation, hyperplasia and fibrosis. More interestingly, although the environmental stimulus disappeared, the epigenetic influence triggered by the initial stimulus still existed, with the phenomenon of "metabolic memory", suggesting that the change of epigenetic mechanism related to environmental stimulation may be the fundamental reason for the continuous progress of complications in diabetes patients, so effective intervention at the level of epigenetic mechanism also reveals new clinical therapeutic targets. The role of epigenetic regulation in the occurrence and development of DN has been reviewed in present paper, including epigenetic differences in DN, and the role of these differences-mediated signal pathway changes on kidney disease, and pay attention to the progress of epigenetic mechanism in treatment of the diseases, so as to provide a basis for clinical diagnosis and treatment of DN through epigenetic mechanism.