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The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. <i>KMT2A</i> rearrangement, <i>DEK-NUP214</i> fusion, and <i>NPM1</i> mutation are associated with the upregulation of <i>HOX</i> genes. The dominant tyrosine kinase activity of the mutant FLT3 or BCR-ABL1 fusion proteins is transduced by the AKT-mTOR, MAPK-ERK, and STAT5 pathways. Concurrent mutations of <i>ASXL1</i> and <i>RUNX1</i> are associated with activated AKT. Both <i>TP53</i> mutation and mis-expressed <i>MECOM</i> are related to impaired apoptosis. Clinical data suggest that adverse genetic factors can be found in at least one in eight AML patients and appear to accumulate in relapsed/refractory cases. <i>TP53</i> mutation is associated with particularly poor prognosis. Molecular-targeted therapies focusing on specific genomic abnormalities, such as <i>FLT3</i>, <i>KMT2A</i>, and <i>TP53</i>, have been developed and have demonstrated promising results.