Locally advanced Head and Neck Squamous Cell Carcinoma (HNC) is a challenging disease for the lack of effective therapies even in the era of molecular medicine (the five-year survival does not exceed 40%). For patients with metastatic and recurrent HNC the standard treatment is the combination of Cetuximab/Platinum and Fluorouracil but median overall survival rate for this population remains lower than 11%. The main reasons of these disappointing outcomes include acquired drug resistance, anti Epidermal growth factors variants, epithelial to mesenchymal transition and tumor hypoxia.Angiogenesis plays a crucial role in HNSCC development and proliferation. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Promising preclinical results with angiogenic inhibitors have engendered a number of trials, but until now there are not yet conclusive data on the value of anti-angiogenic therapy in HNC.