Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected.Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategy.