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Interleukin-6 (IL-6) is a pleiotropic cytokine which plays an important role in a number of cellular processes including proliferation, survival, differentiation, migration and invasion. IL-6 mediates its downstream effects by activating a number of signaling cascades including JAK/STAT, PI3K/AKT and MAPK pathways. In addition to its effects on tumor cells, IL-6 also regulates tumor progression and tumor metastasis by modulating tumor angiogenesis and tumor lymphangiogenesis. A number of studies have shown that IL-6 levels are markedly upregulated in cancer patients. We and others have shown that high IL-6 expression independently predicts tumor recurrence, tumor metastasis and poor survival in head and neck cancer patients. Therefore targeting IL-6 signaling is a potential therapeutic strategy for the treatment of head and neck squamous cell carcinoma (HNSCC). In this review, we discuss the current understanding of the role of IL-6 in HNSCC progression and potential therapeutic strategies to target IL-6 signaling for the treatment of head and neck cancer patients.