Head and neck squamous cell carcinoma (HNSCC) comprise a wide spectrum of neoplasms with different tumor biologies, prognosis and response to therapies. Current tumor classification and traditional diagnostic methods (e.g. clinical assessment, histopathology) are limited in their capacity to determine prognosis and clinical decision-making. Despite recent improvements in treatment, the outcome for patients with HNSCC remains poor. Similar to most tumors, several patient-related factors, (e.g. genetics and environment) and disease-related factors (e.g. tumor location, TMN staging) play a significant role on survival. Thus, the problem in defining the prognosis is that the clinical course and response to treatment differ considerably among patients. Such interindividual variability is related to the heterogeneity of the tumor, genetic and epigenetic variations, thus reflecting the interaction of multiple biological components that result in a unique phenotype. Integrative genomics are developed to identify the molecular pathways leading to cancer at the individual level and find novel prognostic markers for HNSCC, hence tailoring a treatment accordingly. Such genetic-based personalized diagnosis allows tumor stratification and implementation of targeted therapy. Modern medicine includes new drugs that disrupt the implicated molecules and their signaling pathways. Here, we summarize the current state of knowledge that elucidates the translation of genetic data into clinical benefit.