Although immune checkpoint inhibitors (ICIs) have been well integrated into standard practice for patients with some tumor types, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, use of immunotherapy to treat head and neck cancer is more recent. After approvals for nivolumab and pembrolizumab in the setting of recurrent disease several years ago, positive results with pembrolizumab in the front-line have resulted in the approval of the agent for patients with previously untreated metastatic disease. In this activity, we will review the immunology of head and neck cancer and the mechanisms that are thought to underlie the activity of ICIs in this setting. Using a hypothetical patient case scenario, eligibility for immunotherapy will be delineated, including prognostic implications of PD-L1 status, presence and severity of symptoms and tumor burden, and the advantages and risks of monotherapy versus combination regimens. This activity will further examine the potential adverse effects of ICI treatment, such as pembrolizumab, as well as a discussion of appropriate management of those side effects. Finally, we will address future directions, and more broadly, look at investigational agents and novel combinations currently being studied.