Head and Neck Squamous Cell Carcinomas (HNSCC) are a collection of tumors located in the upper aerodigestive tract that account for ∼500, 000 new cases annually. Onset of the disease in the population has been attributed to multiple environmental factors. Pathways leading to the development and progression of head and neck squamous cell carcinomas remain largely unknown. Common genetic alterations have been identified, but many of the important genes of activation (oncogenes) or inactivation (tumor suppressor genes) have not yet been identified or characterized. Epigenetic mechanisms, such as histone modifications and DNA methylation, have also become accepted modes of transcriptional inactivation in human malignancies, but are still in their initial stages of evaluation in HNSCC. The majority of DNA methylation studies in HNSCC have focused on genes previously identified as being inactivated in other cancer types. Efforts using genome-wide methylation scanning techniques, such as Restriction Landmark Genomic Scanning (RLGS), have identified novel methylation targets in HNSCC. Due to the involvement of DNA methylation, clinical trials involving demethylating agents, such as Decitabine, alone or in combination with chromatin modifying agents, remain attractive therapeutic options in cancer currently under investigation. Better understanding of the role of DNA methylation in squamous cell carcinomas of the head and neck, as well as the targets of this epigenetic inactivation, may allow for more efficient and earlier detection screenings. In this review, we will discuss our current understanding of epigenetic alterations in HNSCC and their potential use as targets for therapeutic intervention.