Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent aggressive cancers in humans. Well-known risk factors include HPV infection, tobacco smoking, and alcohol consumption. HNSCC overall survival rate is one of the lowest among human malignancies. The poor prognosis of HNSCC often results from late-stage diagnosis, therapeutic resistance, high rates of recurrence, and frequent metastases to lymph nodes. To date, the TNM classification is still the best evaluation of disease progress; however, this method of staging does not pay attention to the molecular basis of tumorigenesis. An improvement in treatment efficacy and diagnostic capabilities will be realized through a better understanding of the pathogenesis and characteristics of HNSCC, a disease that has come to be characterized by confounding heterogeneity. This chapter is focused on molecular markers derived from key processes of cancero-genesis that are involved in metastasis, treatment resistance, avoidance of immune detection, inflammation, induction of angiogenesis, genome instability, dysregulation of cellular energetics, cell death, cancer stem cell biology, and rearrangement of tissues adjacent to the tumor. We will discuss biomarkers identified at different levels of cellular regulation (DNA, RNA, miRNA, and protein markers).