Head and neck cancers are a group of malignancies with diverse biologic behaviors and a strong, well-established association with tobacco and alcohol use. Although the hunt for genetic alterations in head and neck cancer has continued in the past two decades, with unequivocal proof of a genetic role in multistage head and neck carcinogenesis, epigenetic alteration in association with promoter CpG island hypermethylation has emerged in the past few years as one of the most active areas of cancer research. It is now firmly believed that, in cancer cells, promoter CpG island hypermethylation (epigenetic alteration) represents a bona fide alternative mechanism, as opposed to genetic factors, such as gene mutations and deletion, in the inactivation of many tumor-suppressor genes. It is also realized that epigenetic and genetic factors often work together, affecting multiple cellular pathways, such as cell-cycle regulation, DNA repair, apoptosis, angiogenesis, and cell-to-cell adhesion, during the process of tumor growth and progression.