The epidermal growth factor receptor (EGFR) is playing a role in the multistep carcinogenesis of squamous cell carcinoma of the head and neck (SCCHN) and its signaling promotes SCCHN growth and progression. EGFR is over expressed in the vast majority (>90%) of H&N cases and a high expression is associated with an unfavorable prognosis. Therefore, EGFR is a rational therapeutic target. In practice, both monoclonal antibodies (MAbs), which bind to the outer domain, and small molecule oral tyrosine kinase inhibitors (TKIs) that target the intracellular catalytic domain of the EGFR are being used. Cetuximab (Cet) is the only targeted agent that got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease in association with radiation (RT) and in recurrent/metastatic disease in combination with platinum/5-FU-based chemotherapy (in United States also as single agent in second line) and is still under active investigation in this disease. Unfortunately, several important questions are still unanswered (e.g. is RT + Cet equal in efficacy to RT + cisplatin (P)?, is maintenance therapy essential and for how long?, what are the adequate markers to predict response to Cet?, etc). Moreover, some results have been disappointing (e.g. PRT + Cet is not superior to PRT alone) and some applications are still investigational (e.g. Cet + induction chemotherapy and Cet in the postoperative setting). Interestingly, the results of trials involving other EGFR-directed MAbs, i.e. zalutumumab, panitumumab and nimotuzumab, so far have been consistent with the cetuximab data, but failed their primary end points. The results with EGFR-directed TKIs overall have been disappointing. Dual TKIs of both EGFR and HER/2 (the preferred dimerization partner of EGFR) have shown some promise, as well as newer irreversible HER-family blockers, such as afatinib and PF-299804. Both afatinib and PF-299804 have also demonstrated preclinical activity against tumor cells bearing a truncated EGFR protein, lacking the extracellular ligand-binding domain (EGFR variant III). Despite the hurdles, targeting the HER has a place in SCCHN treatment.