This chapter discusses molecular markers in head and neck cancers, where molecular biomarkers help to stage patients in more meaningful prognostic groups and identify high-risk patients who may benefit from a more aggressive treatment approach. DNA ploidy, chromosomal abnormalities, growth factors, such as epidermal growth factor receptor (EGFR), cell cycle regulatory proteins, p16, p21, cyclin D1, tumor suppressor gene p53, angiogenesis, such as vascular endothelial growth factor (VEGF), and extracellular matrix proteins, such as integrins and laminins are the biologic markers that hold most promise in providing potentially independent information for predicting clinical outcome, early diagnosis and for appropriate treatment. The degradation of extracellular matrix (ECM) is essential for tumor cells to invade surrounding tissues and form metastatic colonies in other distant organs and lymph nodes.