Signal transducer and activator of transcription 3 gene (STAT3) plays an important role in the JAK/STAT signaling pathway induced by cytokine and growth factor receptor activation. STAT3 mutations have been reported in approximately 40% of cases of T-cell large granular lymphocytic leukemia and one third of NK cell lymphoproliferative disorders; these mutations are typically missense mutations or inframe insertions mutations in exons 20 and 21 which encode the Src homology 2 (SH2) domain that mediates the dimerization and activation of STAT protein; these mutations are typically associated with increased transcriptional activity. In addition, the presence of STAT3-mutant T-LGL clones may be found in a subset of patients with aplastic anemia and/or myelodysplastic syndrome. Therapeutic targetting of STAT3 is currently under investigation in various settings.