Although the first reports on a potential association between cancer and the immune system date back to the nineteenth century, the establishment of immunotherapy as an adequate anticancer treatment modality took more than 150 years to complete, being accompanied by many obstacles and challenges. The basic concept behind immunotherapy is to restore the natural anticancer potential of the immune system. In broad terms, immunotherapy includes tumour-specific monoclonal antibodies, cancer vaccines, adoptive cell transfer and immune-modulating antibodies (e.g. immune checkpoint inhibitors). Building on their success in advanced melanoma, immune checkpoint inhibitors have received major attention in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). Pembrolizumab, a monoclonal antibody against programmed death-1 (PD-1) receptor, has been tested in the phase Ib trial KEYNOTE-012 achieving overall response and disease control rates of 25 % and 50 %, respectively. In a phase I/II study with durvalumab, a monoclonal antibody against programmed death ligand-1 (PD-L1), overall response and disease control rates were 11 % and 15 %, respectively. PD-L1 (but possibly also PD-L2) expression and interferon-gamma signature have emerged as promising predictive biomarkers, yet to be prospectively validated. In April 2016, results from a planned interim analysis of the phase III trial CHECKMATE-141 showed a statistically significant improvement in median overall survival (7.5 versus 5.1 months; p = 0.0101) achieved with nivolumab, an anti-PD-1 monoclonal antibody, versus single-agent chemotherapy (methotrexate, docetaxel) or cetuximab, defining thus a new standard of care in platinum-refractory R/M-SCCHN. Due to its distinctive mechanism of action, immunotherapy may not be recommended for patients with comorbid autoimmune disorders and those requiring prompt symptom relief. At present, six other ongoing randomized trials explore immune checkpoint inhibitors in the R/M-SCCHN setting with results to be expected in the first half of 2017.