Head and neck cancers are heavily infiltrated by immune cells, the significance of which is complex. The natural immune response against head and neck tumors, including anti-human papillomavirus (HPV) T cells, and humoral responses has been clearly documented. However, during the course of tumor progression, co-option of the immune system by tumor cells for their own advantage and increased resistance of tumor cells to immune attack also occur. Inflammation and immune subversion to support angiogenesis are key factors promoting tumor growth. Only a better understanding of this tumor-host interaction will permit a rational design of new immunotherapeutic approaches combining immunostimulation with drugs endowed with the ability to counteract immunoevasion mechanisms.