Recently, new targets have been identified in head and neck squamous cell carcinomas (HNSCC) as playing key roles in tumour proliferation and metastases. The first target that has led to the approval of a molecularly based therapy in HNSCC has been the epidermal growth factor receptor (EGFR). Indeed, cetuximab, a monoclonal antibody directed against EGFR, has recently been approved in combination with radiation therapy in patients with locally advanced HNSCC, and in patients with platinum-refractory recurrent or metastatic (R/M) HNSCC. This review discusses novel targeted anticancer agents that do not exclusively target EGFR. The initial assessments of novel agents have typically been in patients with heavily pre-treated R/M HNSCC, with response rates and times to progression that are often disappointing. Evaluation of novel agents in the pre-operative 'window' setting, or as first-line therapy for R/M disease, may offer a more optimal understanding of their molecular and clinical effects.