Throughout the last 2 decades, great strides have been made in managing patients with locally advanced head and neck squamous cell carcinoma. In many clinical settings, they translated to significant advances in treatment efficacy and improvements in disease prognosis. To achieve this, most strategies, ranging from induction to postoperative treatments, are essentially based on multidisciplinary approaches. Nowadays, the indication and sequencing of surgery, radiotherapy, and systemic treatments are carefully weighted in the function of risk levels, efficacy results, and quality of life. Along this track, the coadministration of chemotherapy and radiotherapy was shown, as definitive or adjuvant treatment, to improve the results of conventional radiotherapy alone. However, recent prospective trials showed that the compliance of patients to aggressive approaches is more of a concern for poor tolerability and reduced compliance inevitably impact on treatment dose intensity, leading to the delivery of suboptimal regimens. Therefore, further efforts to tailor novel, multidisciplinary approaches based on drug-radiation interactions have been put forth to optimize treatment outcomes in terms of both disease control and quality of life. Because therapy is becoming more intense, a careful recording and reporting of treatment-related morbidity is also a crucial element in estimating the therapeutic gain from competing strategies. © 2009 Elsevier Inc. All rights reserved.