The addition of cetuximab, a chimeric IgG1 monoclonal antibody (mAb) targeted against the EGFR, to radiation for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) or to platinum-based chemotherapy for patients with recurrent or metastatic (R/M) SCCHN has demonstrated significant gains in overall survival. In contrast, however, it has failed to improve survival when added to concurrent chemoradiotherapy for patients with locally advanced SCCHN. Further investigations are ongoing, including induction chemotherapy followed by radiation concurrently with cetuximab and induction chemotherapy with cetuximab. In contrast, panitumumab, a fully human IgG2 mAb directed against the EGFR, failed to demonstrate significantly improved overall survival when added to platinum-based chemotherapy for patients with R/M SCCHN in a global phase 3 trial. In the predefined analysis by tumor HPV status in this trial, however, panitumumab significantly improved overall survival in patients with HPV- tumors, but not in patients with HPV+ tumors. Although the reason for this failure is not fully clear, recent clinical trials have attempted to exclude patients with HPV+ tumors when adding EGFR mAbs. Afatinib, an EGFR tyrosine kinase inhibitor that irreversibly blocks signaling from all relevant ErbB family dimers, demonstrated comparable anti-tumor activity to cetuximab in patients with R/M SCCHN with progression after platinum-based therapy in a randomized phase II trial. Further investigations in phase III trials are ongoing. Despite the clinical benefit of these EGFR-targeted drugs, they are subject to the development of treatment resistance, indicating the need for novel targeted treatments to improve prognosis. Further investigations aimed at overcoming resistance are ongoing, including clinical trials of combinations with EGFR mAb plus EGFR tyrosine kinase inhibitor or other molecular targeted drugs.