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The treatment of head and neck squamous cell carcinoma (HNSCC) has been a medical challenge with limited improvement in overall survival over the past few decades. However, recently, very interesting innovations in the field of immunotherapy have been shown to be beneficial for patients with advanced HNSCC. In this article, the latest medical developments are reviewed with special focus on the clinical achievements and current clinical studies in the field of immunotherapy. The landscape of clinical studies has changed considerably from antibody-based growth factor inhibition towards immune checkpoint modulation, and new indications in the adjuvant and neoadjuvant setting are being tested in large patient cohorts. Even the combination of 2 or more immune modulatory approaches and the correct synchronization with standard cancer therapy is promising and warrants suitable clinical trials.