Recently new strategies such as the association of chemotherapy with radiotherapy have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: for patients with locally advanced HN-SCC, where outcome with radiotherapy alone is poor. More than one-hundred Phase III trials collected in large meta-analyses have showed that loco regional control and overall survival may be improved at high level of evidence by chemo-radiotherapy especially if delivered with synchronous approach. Sequential or synchronous chemo-radiotherapy regimens can also play a crucial role in larynx-function preservation programs without the risk of overall survival reduction for patients with larynx or hypo pharynx tumors who are candidates to radical surgery. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemoradiotherapy. Despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, awaiting for the results from ongoing trials where chemo-radiotherapy is explored in conjunction with new targeted therapies, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.