Large granular lymphocytic leukemia is a rare disorder marked by expansion of cytotoxic T lymphocytes, often accompanied by autoimmune disease manifestations. Satu Mustjoki and colleagues (N. Engl. J. Med. 366, 1905–1913, 2012) now show that this leukemia subtype frequently harbors somatic activating mutations in STAT3. The authors performed exome sequencing on leukemic and non-leukemic cells from a subject with typical T-cell large granular lymphocytic leukemia and identified a missense mutation affecting the SH2 domain of STAT3. Targeted sequencing in 76 additional cases identified protein-altering STAT3 mutations in 40% of subjects with large granular lymphocytic leukemia. The altered residues cluster at the dimerization interface of STAT3 and are predicted to result in cytokine-independent signaling activity. Consistent with this, STAT3 mutation–positive leukemic cells showed nuclear localization of STAT3 and upregulation of STAT3 transcriptional targets. Transfected cells expressing mutant STAT3 proteins also had increased expression of a STAT-responsive reporter construct. These findings suggest that a substantial proportion of individuals with large granular lymphocytic leukemia could benefit from treatment with STAT3 inhibitors, which are currently being tested in clinical trials for other hematological disorders.