Current development of molecular targeted therapies in oncology is particularly active. The aim of this study is to review recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). As EGFR signaling pathway and angiogenesis play a key role in the growth of HNSCC, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as VEGF and its receptors, represent the main targets of the new therapeutic agents now in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic diseases. Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors and with the development and evaluation of other molecular targeted therapies such as antiangiogenic drugs. As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue.