Throughout the past two decades the efforts to improve the efficacy of treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) have led to increased use of multimodality approaches combining surgery, radiotherapy (RT), and chemotherapy (CT). Conventional RT, a standard approach for locoregionally advanced disease, was associated with unsatisfactory results, thereby, a greater understanding of radiobiology led to the development of two classes of altered radiation fractionation schedules incorporating hyperfractionation (HF) and acceleration in the management of advanced HNSCC. Randomized controlled trials and meta-analyses demonstrated that for patients with locally advanced HNSCC major improvements in locoregional control (LRC) at high level of evidence can be achieved by accelerated fractionation (AF) and HF. For these patients, overall survival (OS) may be improved at high level of evidence by HF delivered with increased total dose. CT represents an important component of multimodality treatment approach for locally advanced HNSCC with concurrent addition of CT to RT being the most significant method for improving head and neck cancer (HNC) outcome. Several randomized studies and meta-analyses on the administration of concurrent chemoradiotherapy (CCRT) demonstrated clear evidence that CCRT provides a substantial and statistically significant improvement in survival and locoregional control, as compared to RT alone. CCRT is now a standard treatment approach for patients with locally advanced HNSCC. CCRT has been also shown to allow organ preservation in almost two thirds of patients without affecting survival. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant CCRT.