Encouraging data for targeted therapy in head-and-neck squamous cell carcinoma are opening new options for treatment. Phase III trials of cetuximab, an antibody directed against the epidermal growth factor receptor (EGFR) have demonstrated benefit in the locally advanced and metastatic settings. Recognizing the importance of emerging therapies, Cancer Care Ontario published guideline recommendations for EGFR-targeted therapy in stage III and IV head-and-neck cancer. The present paper takes a further look at the population for whom an offer of cetuximab therapy may be appropriate.