The advent of immune checkpoint inhibitors (ICIs) has led to dramatic changes in drug therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). ICIs activate cytotoxic T lymphocytes by releasing the inhibitory signals of immune checkpoint molecules that play a role in suppressing excessive immune responses. However, the response rate with ICIs alone is low, and achieving a response takes a relatively long time. Currently, the only drugs approved in Japan for treating R/M SCCHN are the anti-human programmed cell death 1 (PD-1) monoclonal antibodies nivolumab and pembrolizumab. Nivolumab is only approved as a single agent in patients with platinum-refractory R/M SCCHN. In cases where the disease is aggressive or the tumor burden is high, it may be necessary to consider a regimen that includes a cytotoxic anticancer agent or a molecularly targeted agent to achieve a response rate. In addition to the standard EXTREME regimen, regimens for patients with platinum-sensitive R/M SCCHN who have not received chemotherapy include pembrolizumab monotherapy and pembrolizumab plus chemotherapy. Regimen selection is based on the PD ligand 1 combined positive score, which was used as a predictive biomarker of treatment response in the KEYNOTE-048 trial. Even when these ICIs fail, there are cases in clinical practice in which significant tumor shrinkage can be achieved with subsequent drug treatment. In this article, we discuss the appropriate use of these drugs to improve the prognosis of patients with R/M SCCHN.