Head and neck squamous cell carcinoma (HNSCC), a heterogeneous group of upper aerodigestive tract malignancies, is the seventh most common cancer worldwide. Tobacco use and alcohol consumption were the most identified risk factors of HNSCC. However, human papilloma virus, a sexually transmitted infection, has been determined as another primary cause of HNSCC. Early-stage disease is treated with surgery or radiotherapy. Recurrent or metastatic HNSCC is associated with poor prognosis with a median overall survival of 10 months. The EXTREME protocol is commonly used in first-line setting. Recently, pembrolizumab, an anti-programmed death-1 agent, has been approved by the US Food and Drug Administration for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. It demonstrated a durable objective response rate with a good safety profile and quality of life. Many ongoing trials are evaluating the use of pembrolizumab for the treatment of HNSCC in various indications such as adjuvant and neoadjuvant setting, maintenance and recurrent disease, alone or in combination with chemotherapy, radiation and targeted therapy. Finding those biomarkers predictive of response to immune checkpoints inhibitors has been a major concern. However, markers have been identified, such as PD-L1 expression, human papilloma virus infection, interferon-γ signature score, microsatellite instability and neoantigen production.