The term biomarker refers to a host of biologic factors found within a tumor or other clinical specimen that can be used to assess the tumor in some way. Biomarkers have many potential clinical applications. Before they are used in actual clinical settings, however, they must be carefully validated. The literature contains many reports of this ongoing work related to head and neck squamous cell carcinoma. Candidate biomarkers for this disease include the p53 gene and its protein; microsatellite regions throughout the genome; human papillomavirus; proteins involved in cellular proliferation, apoptosis, angiogenesis, and intracellular adhesion; epithelial growth factor receptor; and various measures of immune response to cancer. The best new evidence for the validity of each of these candidates is critiqued in this review.