Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive blood cancer. Genetic abnormalities, such as the t(8
21) rearrangement, play a significant role in AML onset. This rearrangement leads to the formation of the RUNX1/RUNX1T1 fusion protein, disrupting gene regulation and genomic stability, ultimately causing full-blown leukemia. Despite a generally favorable prognosis, t(8
21) patients face relapse and chemotherapy resistance, particularly when harboring cooperating mutations. While advances in cellular genetics and molecular biology have improved AML treatment, there are currently no specific targeted therapies against RUNX1/RUNX1T1. Therefore, investigating targeted therapies for this AML subtype holds promise for patients. This review explores the complex landscape of t(8
21) AML, unravels the molecular mechanisms of RUNX1/RUNX1T1-driven leukemogenesis, and discusses recent advancements in target therapies including small molecule drugs and PROTAC. Our goal is to develop more effective and less toxic strategies for managing t(8
21) AML patients.