The epidermal growth factor receptor (EGFR) has been shown to be a promising therapeutic target in head and neck cancer. Cetuximab, a monoclonal antibody against EGFR, has been approved in the United States for use with radiotherapy for head and neck squamous cell carcinoma. However, the role of EGFR targeting agents in other therapeutic modalities, such as combined chemoradiotherapy or induction chemotherapy, remains to be defined. Although results from several clinical trials have demonstrated the therapeutic potentials of EGFR targeting agents in these settings, further studies are necessary before definitive conclusions can be made. The concurrent targeting of EGFR along with other pathways important in carcinogenesis may hold significant therapeutic potential. In particular, several clinical trials are studying the effects of combining agents that target the vascular endothelial growth factor with EGFR inhibitors. Last, studies are ongoing to elucidate the predictive and correlative biomarkers in anti-EGFR therapy to allow for proper patient selection. In the case of cetuximab, these correlative biomarkers may include elements of the immune system in addition to the signal transduction proteins involved in EGFR pathway.