The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets and mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting -mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.