PURPOSE OF REVIEW: To provide an update on novel compounds in head and neck cancer (HNC) therapy, with emphasis on biologic agents. RECENT FINDINGS: Cisplatin-5-fluorouracil (5-FU) is the standard chemotherapeutic approach in HNC. Strategies to improve its activity include the substitution of 5-FU with oral fluoropyrimidines; the substitution of cisplatin with different analogs or formulations; and the use of additional or alternative compounds. Epidermal growth factor receptor (EGFR) is the most appealing target for novel therapies in HNC. Cetuximab, a chimeric anti-EGFR monoclonal antibody, has undergone evaluation in platinum-refractory recurrent or metastatic HNC with a satisfactory and consistent response rate (10-13%) across three different Phase II studies in association with platinum or as single agent. A recent Phase III placebo-controlled trial has shown better response rate for patients treated with cetuximab and cisplatin, with respect to those treated with cisplatin alone. EGFR tyrosine kinase inhibitors (TKIs) are under investigation in HNC, and efforts are made to understand which molecular features are associated with objective responses. One appealing way to use EGFR TKIs is in combination with other biologic compounds, such as anti-angiogenic agents. SUMMARY: New molecular-targeted therapies are inducing consistent, small improvements in HNC management. The major challenge regards how to better combine them with the final aim of obtaining long-term stabilization of advanced disease.