Squamous cell head and neck cancer (SCCHN) is the seventh most common cause of cancer death worldwide and its incidence is rising rapidly in developing countries. Despite recent advances in managing locally advanced SCCHN, patients with recurrent and metastatic SCCHN have a poor prognosis and little progress has been made its management. Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of SCCHN and is a marker of poor prognosis. Recent advances in targeted therapeutics against EGFR are being investigated clinically. In this article, we review the different modalities utilized to inhibit EGFR signaling in SCCHN, including small molecule tyrosine kinase inhibitors, monoclonal antibodies, anti-sense therapy and immunotoxin conjugates. Monotherapy with EGFR inhibitors has demonstrated response rates between 5 and 15% in advanced SCCHN. However, combining EGFR inhibitors with cytotoxic chemotherapy or radiation therapy appears to augment response rates and survival. With the foundation for the use of EGFR inhibitors laid in these studies, future studies will need to optimize the delivery of these agents in combination with conventional therapies.