Squamous cell carcinoma of the head and neck (SCCHN) is an important source of cancer-related morbidity and mortality worldwide. Current treatment options are founded on various combinations of surgery, radiation therapy, and chemotherapy, with implementation largely based on patient/disease-specific factors and provider/institutional bias. Despite improvements in surgical techniques and the development of novel chemoradiotherapy strategies for organ preservation, survival has remained relatively unchanged in the past 30 years. Additionally, the impact of these novel treatment approaches on the quality of life of patients remains largely unknown. Improvements in survival and the quality of life for patients with SCCHN will likely require the development of new therapeutic alternatives based on the improved understanding of the molecular pathogenesis of SCCHN and associated changes in the immune response.