Despite the remarkable advances in cancer treatment, the 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) has improved only marginally over the past 20 years. Investigators have attempted to develop new therapeutic methods to improve the survival rate from these tumors. Another approach, chemoprevention, has recently been tried to reduce cancer incidence. Biological understanding of tumorigenesis is critically important to provide risk assessment and intermediate end points during chemoprevention trials. Based on the fact that HNSCC develops through a multistep process by the accumulation of genetic and phenotypic changes in the field exposed to carcinogens, the investigation of specific biomarkers that represent each step must be valuable, since these biomarkers could be used to inhibit and/or to reverse the pathway of carcinogenesis. The potential biomarkers are classified as nonspecific and specific genetic biomarkers, proliferation markers, and differentiation markers in this review. Their usefulness in predicting tumors' biological behavior and responses to treatment and in monitoring the preventive effects of chemoprevention trials is also discussed.