Abstract: DNA and histone lysine methylations are the main epigenetic modulatory elements in the development and progression of acute myeloid leukemia. Methylation-targeted therapy includes DNA methyltransferase, methylation modulatory protein, and histonelysine methylation inhibitors. Approved DNA methyltransferase inhibitor (demethylating agent) includes azacytidine and dicitabine, which have been used as antileukemic drug clinically. IDH1/2 inhibitor also showed effective and well tolerated in leukemic patients in phase Ⅱ clinical study. EZH2 inhibitor and LSD1 inhibitor have completed in vitro study and entered clinical trial. Targeting DNA and histone lysine methylations is an alternative approach for leukemia treatment.