Molecular targeted therapies involve biochemical agents that interfere with specific molecules and signalling pathways that are responsible for tumour growth, progression and spread. The major aim of targeted therapies is to better personalise cancer treatment and to increase the therapeutic index by improving tumour control and reducing normal tissue toxicity. Developments in head and neck cancer (HNC) biology have revealed several molecular characteristics that could be used as therapeutic targets. Among them, the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) are probably the most commonly investigated, with several monoclonal antibodies and small molecules being clinically tested to block their effect. As with any other drug, patient selection for targeted therapies is critical, thus biomarker screening is recommended to avoid treating patients that would not benefit from this approach.