During malignant transformation, the malignant cell accumulates epigenetic abnormalities that do not alter the DNA sequence but are transmissible during divisions and modify genes expression. The methylation of CpG islands in the tumor suppressor genes (TS genes) promoters inhibits their transcription ; it is a mecanism of gene inactivation as frequent as allelic deletions. The methylation profile (or panel of methylated genes in a tumor), similarly to allelic deletions, varies with the tumor histology. Within head and neck squamous cell carcinoma (oral cavity, larynx and oropharynx), 19 genes have been analysed, among them 5 are frequently methylated, i.e. : p16, ECAD, DAPK, MGMT et TIMP3. The method of methylation analysis, based on a bisulfite treatment followed by a PCR amplification, is sensitive and specific enough to allow the detection of abnormalities in biological fluid that drain the tumor or in circulating tumoral DNA. In the head and neck squamous cell carcinoma, correlation between the methylation profile in tumor and paired saliva is excellent ; thus methylation analysis in saliva is a very promising approach for early cancer detection in high risk patients or for the post treatment follow up and rapid diagnosis of relapse. The methylation signature might also reflect the tumor prognosis and complete the histology to define the diagnosis. Finally, DNA methylation is reversible with demethylating agents, a new avenue for cancer therapy in association with conventional chemotherapy.