AbstractWe present the molecular landscape of pediatric acute myeloid leukemia (AML), characterizing nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG/NCI TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA, miRNA sequencing and CpG methylation profiling. Validated DNA variants revealed diverse, infrequent mutations with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including novel gene fusions and focalMBNL1,ZEB2, andELF1deletions, were disproportionately prevalent in young as compared to adult patients. Conversely,DNMT3AandTP53mutations, common in adults, are conspicuously absent from virtually all pediatric cases. NovelGATA2,FLT3, andCBLmutations, recurrentMYC-ITD, NRAS, KRAS, andWT1mutations are frequent in pediatric AML. Deletions, mutations, and promoter DNA hypermethylation convergently impact Wnt signaling, Polycomb repression, innate immune cell interactions, and a cluster of zinc finger genes associated withKMT2Arearrangements. These results highlight the need for, and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.