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Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Classically, it is a disease related to tobacco and alcohol use; an increasing number of patients are being diagnosed with HNSCC caused by infection with the human papillomavirus. New deep-sequencing techniques have confirmed the importance of p53 and EGF receptor in HNSCC development, and have identified pathways of critical importance, such as PI3K/mTOR and NOTCH. Increasing knowledge of key molecular features has lead to new therapeutic avenues for HNSCC. Novel therapies under investigation in HNSCC include antibody and small molecule inhibitors of EGF receptor and its family members, PI3K inhibitors, antiangiogenic agents, immunotherapies and agents interacting with early developmental pathways such as Hedgehog.