Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive disease with multiple mechanisms to impair immune-mediated recognition and control of tumor cell proliferation and metastasis. Based on successes experienced with cancer immunotherapy in the treatment of other solid tumors, considerable efforts are underway to develop immunotherapeutics that can enhance the host antitumor response to HNSCC. Promising results in preclinical studies and early clinical trials have been reported, prompting the FDA to approve the use of the immune checkpoint PD-1 receptor antagonist pembrolizumab for the treatment of platinum-refractory recurrent or metastatic HNSCC in 2016. Ongoing clinical trials are investigating the use of various immunotherapies, such as vaccines, adoptive T-cell transfer, and immune modulating antibodies alone or in conjunction with traditional treatment modalities, to achieve more efficacious, more durable, and less toxic treatments. In this article, we provide a basic review of the role of the immune system in developing malignancy, and we discuss some notable mechanisms of immune evasion in HNSCC. We highlight current approaches and published clinical results of immunotherapy in the treatment of HNSCC.