KMT2A-rearranged (KMT2A-r) and NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) share a dependency on the menin–KMT2A interaction. Menin inhibitors have produced clinically meaningful remissions, but primary resistance, persistent measurable residual disease (MRD), and relapse limit durability. Acquired MEN1 drug-pocket mutations that impair inhibitor binding while preserving menin–KMT2A function are currently the best-established clinical mechanism of resistance. Other proposed routes—including epigenetic or signaling bypass, altered apoptotic dependence, metabolic adaptation, persistent cell states, and microenvironmental protection—are supported to varying degrees by functional preclinical studies or broader AML biology and remain incompletely validated in longitudinal patient samples. The evidence for individual mechanisms also differs between KMT2A-r and NPM1-mut AML. This review evaluates the hierarchy and subtype specificity of current evidence, distinguishes validated clinical observations from emerging concepts, and discusses biomarkers and investigational strategies for prospective evaluation. Standardized NPM1 molecular MRD provides an established monitoring framework, whereas KMT2A-r molecular monitoring is more heterogeneous and often fusion- or patient-specific. Integrating validated MRD methods with research pharmacodynamic and clonal assays in prospective studies will be essential for determining which resistance mechanisms are clinically actionable.