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In hematological malignancies, particularly myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML), TLRs influence inflammation, disease progression, and therapeutic response. This review highlights the prognostic relevance of TLR expression, the role of the MyD88 signaling pathway in clonal evolution, and the dual nature of TLR\u2010mediated immune responses, either promoting antitumor activity or contributing to leukemogenesis. Notably, TLR dysregulation in MDS and AML is associated with poor prognosis and genomic instability, whereas in CML, TLRs contribute to a protective microenvironment via NOD\u2010like and TNF\u2010\u03b1 pathways. Therapeutic strategies targeting TLRs, including agonists and antagonists, show promise in enhancing antitumor responses, especially when combined with agents like purine nucleoside phosphorylase inhibitors. 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