Abstract HMPL-306 (Ranosidenib), a novel dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (mIDH1/2), emerges as a transformative therapeutic strategy for cancers harboring mIDH mutations, addressing critical limitations of single-target therapies. By concurrently inhibiting mIDH1/2, HMPL-306 circumvents isoform switching, a key resistance mechanism and potently suppresses the oncometabolite 2-hydroxyglutarate (2-HG), a driver of tumorigenesis and epigenetic dysregulation. In relapsed/refractory acute myeloid leukemia (AML), where mIDH1/2 mutations are prevalent, early clinical trials report complete remission rates with partial hematologic recovery (CRh) exceeding 30%, outperforming single-IDH inhibitors. Its unmatched CNS penetration, evidenced by a high brain-to-plasma ratio, positions HMPL-306 as a pioneering therapy for gliomas and CNS malignancies, overcoming the blood-brain barrier challenges that hinder current treatments. Beyond hematologic and CNS cancers, preclinical studies underscore its efficacy in mIDH-driven solid tumors, including cholangiocarcinoma and chondrosarcoma, highlighting broad therapeutic applicability. The agent’s favorable safety profile, marked by minimal off-target effects and reduced hematologic toxicity, further enhances its clinical utility. As combination therapies gain momentum, HMPL-306’s dual inhibition offers a synergistic backbone for integrating with chemotherapy, hypomethylating agents, or immunotherapy, potentially redefining treatment paradigms. This review synthesizes HMPL-306’s mechanistic innovation, clinical promise, and translational potential, advocating its role as a cornerstone in precision oncology for diverse mIDH-mutated cancers. Ongoing trials and biomarker-driven approaches may further unlock its capacity to improve outcomes in malignancies with historically limited options.