Simple SummaryTherapeutic advances in acute myeloid leukemia (AML) are dependent on identifying and targeting the molecular aberrations that drive disease. The European LeukemiaNet (ELN) 2022 guidelines have improved the categorization of AML into distinct molecular subgroups. One of the most notable recent inclusions is a group of mutations highly specific for secondary AML. This review examines how each of the secondary-type mutations contributes to the genesis of leukemia while spotlighting potential therapeutic avenues. While we highlight the limitations of the ELN 2022 revision, we also emphasize current progress, recent breakthroughs, and novel therapeutic options tailored to each molecular subset. This review provides a background and foundation for rational molecular-based therapeutic approaches and combination strategies to inspire future clinical trial designs.AbstractThe characterization of the molecular landscape and the advent of targeted therapies have defined a new era in the prognostication and treatment of acute myeloid leukemia. Recent revisions in the European LeukemiaNet 2022 guidelines have refined the molecular, cytogenetic, and treatment-related boundaries between myelodysplastic neoplasms (MDS) and AML. This review details the molecular mechanisms and cellular pathways of myeloid maturation aberrancies contributing to dysplasia and leukemogenesis, focusing on recent molecular categories introduced in ELN 2022. We provide insights into novel and rational therapeutic combination strategies that exploit mechanisms of leukemogenesis, highlighting the underpinnings of splicing factors, the cohesin complex, and chromatin remodeling. Areas of interest for future research are summarized, and we emphasize approaches designed to advance existing treatment strategies.