The upper aerodigestive tract is predisposed to the formation of multiple primary tumors due to field cancerization. TGF-alpha/EGFR autocrine signaling appears to play an important role in squamous cell carcinoma of the head and neck (SCCHN) and upregulation of TGF-alpha and EGFR is an early event in SCCHN carcinogenesis. STAT proteins, including Stat3, are activated by TGF-alpha and EGFR and strategies that downmodulate TGF-alpha or EGFR inhibit SCCHN cell proliferation and abrogate Stat3 activation. Targeting Stat3 leads to SCCHN growth inhibition, increases apoptosis and a downmodulation of Bcl-xL expression in head and neck tumors. These studies support the role of Stat3 as an oncogene, which is activated early in SCCHN carcinogenesis, and efforts to understand EGFR-mediated Stat3 signaling could facilitate novel strategies that will interfere with this growth promoting pathway. Oncogene (2000).