Abstract: Acute myeloid leukemia (AML) is characterized by marked biological heterogeneity, and molecular classification is essential for therapeutic decision-making and prognostic stratification. With the advancement of precision oncology, genotype-directed targeted therapy has emerged as a critical element in the management of AML. Although KMT2A rearrangements and NPM1 mutations arise from distinct molecular events, both converge on aberrant activation of the HOX/MEIS1 transcriptional program, thereby sustaining the self-renewal of leukemic stem/progenitor cells and impairing myeloid differentiation to promote leukemogenesis and disease progression. Menin, encoded by the tumor suppressor gene MEN1, functions as a nuclear scaffold protein and serves as an essential mediator for the assembly of KMT2A fusion-driven transcriptional complexes, recruitment of cooperative cofactors, and stabilization of oncogenic transcriptional networks. The disruption of the Menin-KMT2A interaction represents a mechanistically grounded therapeutic strategy. In recent years, multiple Menin inhibitors have progressed to clinical development and exhibited clinically significant activity in AML subsets with KMT2A rearrangements or NPM1 mutations. This review summarizes current progress in the research and clinical application of Menin inhibitors in AML, focusing on pharmacological mechanisms, efficacy and safety profiles derived from clinical studies, and emerging resistance mechanisms, including recurrent MEN1 hotspot mutations and epigenetic/transcriptional reprogramming. We further discuss rational combination approaches and directions for the development of next-generation agents, aiming to enhance clinical practice and guide future research.