The integration of targeted therapies into clinical practice constitutes the paradigm of oncology treatment in the current era. Cetuximab, a recombinant human/mouse chimeric epidermal growth factor (EGFR) monoclonal antibody is a targeted agent that has seen expanding indication in recent years. Originally approved for colorectal cancer, its role in the treatment of squamous cell carcinoma of the head and neck has augmented treatment options for patients who are refractory to or cannot tolerate platinum. This article will review the science underlying cetuximab, data supporting its use in patients with locally advanced and recurrent/metastatic disease, common toxicities of therapy, and the integration of this treatment with radiation therapy.