Squamous cell carcinoma of the head and neck affects more than 500,000 people worldwide each year. Local-regional recurrence of disease is a common and challenging oncological problem in patients affected by this disease. Identification of risk factors for local relapse after appropriate local therapy with surgery, radiation, or combination therapy remains an active area of clinical research. The recent development of novel molecular markers has resulted in numerous studies evaluating the prognostic significance and potential clinical utility of these markers in identifying patients at risk for local-regional relapse. This article reviews recent studies evaluating molecular markers, including p53, angiogenesis-related markers, cyclin D1, epidermal growth factor receptor, loss of heterozygosity, DNA ploidy, and cell kinetic markers. The potential clinical utility of these markers and future directions along this avenue of investigation are discussed.