Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non–small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations. (Cancer Res 2006; 66(6): 3162-8)