Pathogenic alterations of are an independent poor prognostic factor in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clinical course of - altered myeloid neoplasms is dictated by genetic characteristics, such as allelic state and variant allele frequency (VAF), and not the blast count. Hence, it was recently proposed that MDS (with increased blasts) and AML with alterations may be best classified as a single molecular disease entity, -mutated higher-risk (HR)-MDS/AML. mutations drive resistance to intensive chemotherapies and less intensive hypomethylating agents (HMA). Novel combinations incorporating BCL2 inhibitor venetoclax improve response rates for -mutated subgroup, but the survival is not improved. Early clinical studies combining HMA with investigational agents demonstrated activity in -mutated HR-MDS/AML, but updated results with larger samples, longer follow-up, or randomized trials were less impressive to date. Future research should focus on finding novel, potentially disease-modifying therapies to improve outcomes in patients with -mutated HR-MDS/AML.