Initial research showed that EGFR targeting through known single agents, both monoclonal antibodies and small-molecule tyrosine-kinase inhibitors, applied to patients with refractory head and neck cancer, resulted in low response rates and short median survival times. However, the combination of Cetuximab with radiotherapy in patients with locally advanced disease and with a combination of platinum and fluorouracil in the setting of relapsed and/or metastatic disease resulted in a sharp improvement compared to standard therapy. Cetuximab entered clinical practice in both indications. Other anti-EGFR drugs, although showing activity, have not demonstrated an improvement of the results of standard therapy. Unfortunately, no molecular parameter emerged as a useful tool in predicting activity, thus impairing clinical applications. Only skin rash was repeatedly shown to be related with drug activity. Although generally well tolerated, class and drug specific toxicities can be troublesome and require knowledge and expertise for an optimal management. Further research is needed in order to find the best ways of integrating the anti-EGFR strategy with current standards of care.