Despite the policy changes to decrease tobacco consumption and therapeutic advances in this disease, squamous cell carcinomas arising from the head and neck (HNSCC) continue to represent a common neoplasm and a leading cause of cancer-related mortality in Europe and worldwide. although different approaches have been evaluated, no treatment has currently been shown to be superior to cisplatin (Platinol, Corden Pharma) based chemoradiation in locally advanced HNSCC. Based on retrospective subgroup analyses from multiple large clinical trials, human papillomavirus (HPV) status has been shown to be a validated prognostic factor in oropharyngeal tumors. Patients with HPV-related tumors, especially those who are non-smokers, have generally excellent outcome as their tumors are highly sensitive to both chemotherapy and radiation, whereas those with tobacco-related and HPV-negative tumors, who continue to represent substantial number of cases in Europe, have worse prognosis with tumors that are more resistant to treatment. The goal of treatment de-intensification in patients with favorable risk is to avoid long-term and late toxicity, but this must be achieved without compromise of treatment efficacy. For those with risk factors that portend a worse prognosis, the question remains whether addition to or modification of conventional treatment regimens would improve upon therapeutic index. Innovative clinical trial designs specifically tailored to these risk groups are urgently needed.