Systemic chemotherapy is increasingly being used with radiotherapy for the radical treatment of advanced head and neck cancers. Chemotherapy offers modest benefits in the metastatic setting. Platinum containing agents are the most active drugs and form the mainstay of most chemotherapy schedules. In recent years taxanes have shown activity in head and neck cancers and are being -incorporated into neo-adjuvant and concomitant chemotherapy regimens. Targeted agents and epidermal growth factor receptor (EGFR) inhibitors, like cetuximab, in particular, have shown benefit in the metastatic and the concomitant setting. EGFR inhibitors and other targeted agents form the thrust of pre-clinical and clinical research into the systemic treatment of head and neck cancers.