Treatment of unresectable, locally advanced head and neck cancer consists of many different options, all of them based on radiotherapy. The main variable is represented by chemotherapy, i.e., the way in which chemotherapy is combined with radiation. More recently, the combination of cetuximab and radiotherapy emerged as a new treatment opportunity and induction chemotherapy, with the combination of docetaxel, cisplatin, and 5-fluoruracil, gained a renewed interest. Concurrent chemoradiation is based on the most robust evidence and is regarded as the leading standard of care for unresectable locally advanced head and neck cancer. Unfortunately, chemoradiation is hampered by severe toxicity and patients must be selected carefully before treatment. The experience of the staff (medical oncologists, radiation oncologists, and nurses), and in particular its familiarity with toxicity management, as well the structural facilities, play an important role in the final outcome. When the patient is unfit for chemoradiation, or when experienced staff or adequate structures are unavailable, induction chemotherapy, cetuximab and radiotherapy, or radiotherapy alone are all evidence-based alternative options. The choice among them will be based on the clinical condition of the patient, the physician's experience, and the patient's preference. Whatever is the treatment of choice, it is important to involve a multidisciplinary staff in the management of these patients. Indeed, also unresectable patients may require supportive surgical interventions before or during treatment, or removal of residual disease after treatment.