Diethylnitrosamine (DEN) is highly toxic to both human and animals, even the parenteral or oral administration of the smallest quantities results in severe liver damage. Due to the robustness of the induced hepatic alterations, the application of DEN in rodents has become an attractive experimental model for studies aimed at understanding the pathogenetic alterations underlying the formation of liver cancer. The liver injury induced by DEN in mice can cause liver cirrhosis and tumors, which makes it an ideal animal model to analyze the pathogenesis and process of human hepatocellular carcinoma. However, some studies have indicated that the carcinogenic effect of Diethylnitrosamine may be related to the different genetic background, gender, age and other factors. Therefore, this article reviews the relevant literatures, in order to establish a stable, high success rate, low mortality DEN model, and to provide references for different purposes.