Core Tip: Immune checkpoint inhibitors have demonstrated better survival outcomes and acceptable toxicity profiles in recurrent/metastatic head and neck squamous cell carcinoma in the first and second-line treatment settings. While anti- programmed cell death protein-1 agents demonstrated efficacy, evidence on the effectiveness of anti-programmed death ligand-1 and anti-cytotoxic T lymphocyte-associated antigen-4 agents is lacking. There is no proven efficacy in the curative setting to date. Gaps in knowledge were found in terms of predictive biomarkers and identification of patients who would benefit from immunotherapy based on biomarker assessment. Several promising trials are currently ongoing to fill this knowledge gap. Novel combination strategies to potentiate and prolong the anti-tumor activity of immune checkpoint inhibitors are also being evaluated currently.