Abstract: Aberrant DNA methylation is one of the most common epigenetic changes in malignant tumor. It plays an important role in gene expression regulation and genome stability, which are closely correlated with the initiation and progression of leukemia. The analysis of DNA methylation of tumor-related genes may be served as a biomarker for detecting minimal residual disease and assessing the risk of recurrence of leukemia. Thus, it would be important to induce demethylation of tumor suppressor gene in researching anti-tumor drug. This review focuses on the relationship between DNA methylation and initiation of leukemia, and the research advances of demethylation-related therapy for leukemia.