Most patients with head and neck squamous cell cancer (HNSCC) will present with advanced disease characterized by poor prognosis and limited treatment options. Our growing understanding of the complex crosstalk between tumor cells and the immune system has facilitated the development of promising therapies targeting immune checkpoints, such as programmed death 1 and the cytotoxic T-lymphocyte antigen 4, which are producing considerable clinical responses. However, HNSCC tissues use diverse strategies to avoid immunosurveillance, thus limiting our ability to fully harness the immune system to achieve consistent and durable antitumor activity. This may be counteracted by optimizing the dosing, sequence, and timing of immune checkpoint therapies and by combining these regimens with other modalities such as radiation therapy, cancer vaccines, cytotoxic chemotherapies, and molecularly targeted agents. The present review summarizes the pathophysiological role of immune regulation in HNSCC and provides a concise update on the clinical translation of immune checkpoint therapies in this tumor type.