Squamous cell carcinoma of the mucosal surfaces of the head and neck area exhibits a complex interaction with the host immune system that plays an important part in the evolution of the malignant process, in the resistance to different therapeutic modalities, and the ability of tumor cells to metastasize to distant organs. The recent advances in tumor immunology have transformed the field in onco-immunology from using non-specific immune-stimulant agents such as interferon and interleukins to the area of rationally targeted immunotherapy such as immune checkpoint inhibitors, which have shown promising results in early phase clinical trials.