The transcription factors STAT3, STAT5A, and STAT5B are essential regulators of hematopoiesis and immunity, yet their aberrant activation drives acute myeloid leukemia (AML) and natural killer/T-cell lymphoma (NKCL). Current therapeutic approaches largely target upstream tyrosine kinases to indirectly inhibit STAT3/5, but these kinase inhibitors lack selectivity and are prone to resistance. Pölöske et al. instead developed dual-specific STAT3/5 degraders that directly target both transcription factors for degradation, and demonstrate that this approach effectively blocks disease progression in preclinical models of AML and NKCL. By bypassing the limitations of kinase-focused strategies, this work positions direct STAT3/5 degradation as a promising and more selective therapeutic avenue for STAT3/5-driven hematologic malignancies.