We discuss the results of the phase III EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) trial. In this study, 442 untreated patients with advanced squamous cell carcinomas of the head and neck (SCCHN) were randomly assigned to receive platinum and 5-fluorouracil with or without cetuximab. Median overall survival -- the primary end point of the trial -- was improved in the cetuximab arm compared with the chemotherapy-alone arm (10.1 months and 7.4 months, respectively; P = 0.04). This is the first phase III trial in over two decades to exhibit a survival advantage in patients with SCCHN not amenable for curative treatment; however, it raises several considerations for clinical practice and future research directions, such as the optimum choice of chemotherapy to be combined with cetuximab, sequencing of cetuximab with chemotherapy, predictive markers of benefit from cetuximab, as well as implications for patients with locally advanced, potentially curable disease.