Squamous cell carcinomas of the upper aerodigestive tract exhibit complex interactions with the host immune system that may simultaneously explain resistance to various therapeutic modalities and that may also provide opportunities for therapeutic intervention. The interplay between developing or established malignancy and the host immune system is best understood through a careful analysis of the key components and effector arms of the immune system. These include the complex cellular network of immune modulation as well as tumor-derived factors such as chemokines and cytokines. While the host response to the developing tumor may successfully curtail tumor growth in some cases (immunosurveillance), squamous cell carcinomas of the head and neck are characterized by their ability to create an immunosuppressive environment powerful enough to evade the immune response. It is increasingly apparent that efforts to stimulate a therapeutically effective immune response against established tumors must be coupled with strategies to abrogate this immune-suppressive environment. Preclinical studies and clinical trials have yielded promising results and provide the foundation for further refinements in a broad variety of immunotherapeutic strategies targeting all components of the immune system. Combining such approaches with the established treatment options of surgical resection, radiotherapy, and chemotherapy may ultimately yield substantive improvements in overall survival that to date have been lacking and simultaneously reduce disease-related and treatment-related morbidities for this debilitating and deadly disease.