Expression of EGF receptor (EGFR) is frequently elevated in squamous cell carcinoma of the head and neck (SCCHN). Cetuximab is an anti-EGFR monoclonal antibody that has been shown to improve overall survival in patients with locally advanced SCCHN when combined with radiotherapy. Data from Phase II trials suggest an interesting activity of cetuximab in patients with recurrent or metastatic SCCHN who are refractory to cisplatin. The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) Phase III trial compared platin-5-fluorouracil alone versus combined with cetuximab as first-line treatment in recurrent or metastatic SCCHN. In the cetuximab arm of this study, a significant improvement in the overall survival (the main objective), progression-free survival and response rate were observed. The quality of life analyses (QLQ-C30 and QLQ-H&N35) showed no significant differences in most of the studied scores between the two treatment arms. Nevertheless, patients in the cetuximab arm displayed significant improvements in pain, swallowing problems and scores for speech and social eating problems. The results of the EXTREME study (and other studies evaluating cetuximab for the treatment of SCCHN) suggest a lack of a predictive value for the expression of EGFR (determined by immunohistochemistry) by the tumor and other biomarkers need to be investigated. The role of other targeted drugs and of possible combinations of these new drugs with cetuximab should be investigated in properly designed preclinical studies and clinical trials.