While a large proportion of patients presenting with stage I and II squamous cell carcinoma of the head and neck (SCCHN) will remain disease free after single modality treatment, the majority of patients presenting in a more advanced disease stage and very often treated with a form of combined modality treatment, will eventually relapse, either locoregionally only, at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Prognostic factors analysis in such patients treated with (platinum-based) chemotherapy has identified five adverse prognostic factors, which seems worthwhile to take into consideration when performing trials; one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG performance status, weight loss, location of the primary tumor and prior radiotherapy). Moreover, it has been shown that response to systemic therapy has a major impact on survival. None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice.