The signal transducer and activator of transcription (STAT) proteins relay signals from cytokine receptors and receptor tyrosine kinases on the cell surface to the nucleus, where they affect the transcription of genes involved in normal cell functions, including growth, apoptosis and differentiation. STAT3 has been found to be constitutively active in head and neck squamous cell carcinoma (HNSCC) as well as in other epithelial malignancies. In HNSCC, STAT3 alters the cell cycle, prevents apoptosis, and mediates the proliferation and survival of tumour cells. Several therapeutic approaches are being developed to target STAT3, including molecules that block either dimerisation or DNA binding by STAT3, strategies to decrease STAT3 expression and drugs that inhibit STAT3 function. Strategies that block STAT3 may prove efficacious for cancer treatment.