Beside the surgical treatment of head and neck cancer, the concept of organ and function preserving therapy of locally advanced HNSCC (head and neck squamous cell carcinoma) especially of oropharyngeal origin is becoming increasingly important. The comparison of induction chemotherapy plus chemoradiation and primary concomitant chemoradiation has recently been the subject of randomized clinical trials. New combinations of different (chemo)radiation regimens and targeted therapies are also under investigation for HNSCC. Molecular markers predicting treatment efficacy as well as new potential targets are also being evaluated in several clinical trials. The good prognosis of HPV-associated HNSCC has sparked efforts to deintensify treatment to minimize therapy-related toxicities. The impact of specific therapies is growing due to the increasing incidence of young patients with HPV-positive carcinomas.