The lysine methyltransferase 2A (KMT2A) gene, also known as the mixed lineage leukemia (MLL) gene, is involved in normal hematopoiesis and metabolism in humans. KMT2A-rearranged acute myeloid leukemia (KMT2A-r AML) is a specific type of AML characterized by high malignancy. It is insensitive to the conventional AML chemotherapy regimen of anthracycline daunorubicin (DNR) combined with cytarabine (Ara-C) "3+7", resulting in low remission rates and high relapse rates. In recent years, preclinical and clinical studies on KMT2A-r AML have been progressively undertaken. At present, the Menin inhibitor revumenib is the first targeted drug approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory KMT2A-r acute leukemia, and research on the DOT1L inhibitor pinometostat in combination with various other drugs is ongoing. Additionally, hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T-cell (CAR-T) therapies have been subjects of clinical application studies. This article will review the pathogenesis of KMT2A-r AML, targeted drugs, ongoing clinical trials, potential therapeutic targets, and the application of HSCT and CAR-T therapies, aiming to provide new perspectives for the research and treatment of this condition.