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Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.