Chemotherapy can be administered in patients with locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) either concurrently with irradiation or as induction chemotherapy prior to local treatment or as palliative therapy in patients with recurrent and/or metastatic disease. Cisplatin-based chemoradiation is still the standard for LA-SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is indicated. Areas of active investigation in LA-SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil in recurrent/metastatic disease. Combination chemotherapy in this setting is preferably used in younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. However, a survival benefit was observed when cetuximab was combined with platinum-5-fluorouracil.