The long-term survival rates for patients diagnosed with advanced head and neck cancer (HNC) remain poor. Many perplexing factors, including etiology and comorbidity, lead to different molecular malfunctions of HNC cells and determine the prognosis of the disease. Traditional diagnostic methods are limited in that they fail to provide an effective classification diagnosis, such as a more precise prediction of prognosis and decisions for personalized treatment regimens. Recently, molecular biology techniques, especially epigenetic and genetic techniques, have been developed that have enabled us to gain a greater insight into the molecular pathways underlying the cancers. Translating the research into a format that will facilitate effective molecular classification, support personalized treatment and determine prognosis remains a challenge. In this review, the authors provide an overview of cancer epigenetic and genetic alterations, tissue banks, and several promising biomarkers or candidates that may ultimately prove to be beneficial in a clinical setting for patients with HNC.