Survival of head and neck cancer (HNC) patients has not dramatically improved over the last 30 years, despite the advances in surgical techniques, chemotherapeutic agents and radiotherapy treatment planning and definition. Different studies in molecular biology of HNC have been carried out, providing useful results for clinical application. HNC usually includes malignant tumors arising from mucosa of the upper aerodigestive tract, from nasopharynx to larynx/trachea, while salivary gland and thyroid cancers are less frequently listed in this classification. In this review, we chose to provide a comprehensive review of the role of biological agents in head and neck subsites. Molecular characteristics and treatment-relevant signaling pathways will be briefly discussed along with the results of the more recent clinical studies that include biological agents.