Epidermal growth factor receptor (EGFR) is a cell membrane protein that is overexpressed in almost all head and neck squamous cell carcinomas. Overexpression of EGFR has been associated with a poor prognosis in head and neck tumors as well as many other malignancies. This cell membrane protein has been considered an excellent choice as an antitumor therapeutic target. Preclinical and clinical investigations are currently underway to determine the most appropriate use of anti-EGFR therapies. IMC-C225 is a monoclonal antibody that blocks EGFR function and has shown promising radiosensitizing and chemosensitizing properties in preclinical studies. Additionally, initial phase I/II clinical studies of IMC-C225 in combination with radiotherapy or chemotherapy have suggested that the preclinical findings may translate into promising clinical results in squamous cell carcinoma of the head and neck. Therefore, patients with head and neck carcinomas are being evaluated in phase III studies exploring the combination of IMC-C225 and radiation as well as the combination of IMC-C225 and cisplatin in locally advanced and recurrent disease.