BACKGROUND: Nuclear factor-kappaB (NF-kappaB), a transcription factor known to modulate expression of factors involved in inflammation, immunity, proliferation, and apoptosis, is constitutively activated and plays a role in pathogenesis and therapeutic resistance in head and neck squamous cell carcinoma (HNSCC). Understanding the molecular alterations leading to aberrant NF-kappaB activation in HNSCC may direct investigators to novel therapeutic targets. METHODS: Results of laboratory and clinical studies are reviewed. RESULTS: The structure, function, and activation of NF-kappaB, products of NF-kappaB target genes and their role in HNSCC oncogenesis, and current NF-kappaB modulating interventions are described. CONCLUSIONS: Aberrant NF-kappaB activation contributes to the expression of oncogenes and the malignant phenotype observed in HNSCC. NF-kappaB, along with providing a link between cancer and inflammation, may serve as an appropriate therapeutic target to inhibit tumor growth and sensitize cancer cells to established cytotoxic anticancer therapies.