Context .- Radiation is a key arm in the multidisciplinary treatment of patients with head and neck squamous cell carcinoma. During the past 2 decades, significant changes in the way radiation therapy is planned and delivered have improved efficacy and decreased toxicity. Refined approaches in the application of radiation and chemoradiation have led to organ-sparing treatment regimens for laryngeal and pharyngeal cancers and have improved local and regional control rates in the postoperative, adjuvant setting. The molecular and genetic determinants of tumor cell response to radiation have been studied, and several potential biomarkers are emerging that could further improve application and efficacy of radiation treatment in head and neck squamous cell carcinoma. Objective .- To discuss the current understanding of potential biomarkers related to radiation response in head and neck squamous cell carcinoma. Data Sources .- Existing published literature. Conclusions .- Several potential biomarkers are actively being studied as predictors and targets to improve the use and efficacy of radiation therapy to treat head and neck squamous cell carcinoma. Several promising candidates have been defined, and new markers are on the horizon.