Head and neck squamous cell carcinoma arises from a clonal population of cells that accumulate many genetic alterations in a multistep process. Each of these alterations may give these cells a growth advantage to allow them to progress toward malignant transformation. These alterations preferentially appear in a different stage of the carcinogenesis. The identification and characterization of these changes may not only provide insights into tumor biology, but also provide markers for many potential clinical applications. Progress in the identification of new biomarkers and their applications over the past 2 years is reviewed.