Recurrent and metastatic squamous cell carcinoma of the head and neck still carries a poor prognosis. Response rates with combination chemotherapy regimens are generally higher than those observed with single-agent chemotherapy. However, this did not translate into an overall survival benefit, not in even a single randomized trial. As none of the combination chemotherapy regimens demonstrated an overall survival benefit when compared with single-agent methotrexate, cisplatin or 5-fluorouracil, the use of combination chemotherapy outside clinical trials is usually restricted to younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. After decades without real progress, a recent randomized trial showed that adding cetuximab, the first clinically available EGF receptor-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil), led to an important survival benefit. In addition, the response rate nearly doubled with this approach, which has great promise for the treatment of symptomatic disease. There is now a plethora of targeted therapies in various stages of preclinical and clinical development. The next challenge will be to sort out which of them have a clinically meaningful activity and find out how to incorporate them into existing treatment regimens.