The estimated annual incidence of oral cavity and pharyngeal cancer is 39,000 in the United States and 260,000 cases worldwide. Despite significant advances in surgery, chemotherapy and radiotherapy, the 5-year survival rate for locally advanced head and neck tumors remains at 50 %. With further intensification of existing treatment limited by the already significant morbidity of multi-modality treatment, there is a clear need for novel therapeutic strategies [1]. Accumulating evidence suggests that the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC) is highly immunosuppressive, mediated by soluble and cell-associated inhibitory mediators and recruitment of host immunosuppressive cells. Thus, understanding and reversing the specific mechanisms underlying tumor-mediated immunosuppression in HNSCC is an important approach to generating an effective antitumor immune response, either as a component of immune-based therapy or as a complement to conventional treatment approaches. This article outlines significant immune-suppressive mechanisms in the HNSCC tumor microenvironment and potential approaches to enhancing the antitumor immune response.