Head and neck squamous cell carcinoma affects more than 500,000 people worldwide each year. Despite optimal treatment with surgery, irradiation, and chemotherapy, disease recurrence and progression remains a common and challenging oncological problem. Recently, interest has developed in identifying novel molecular markers that allow identification of those patients at increased risk for locoregional recurrence and death. This article reviews several such molecular markers studied in head and neck cancer, including p53, angiogenesis-related markers, cyclin D1, and epidermal growth factor receptor. The biological function of these markers and the potential clinical implications are discussed. The purpose of this review is to update the otolaryngologist on a rapidly emerging segment of applied translational research in our field.