Therapeutic outcomes of the currently used chemotherapeutic agents for recurrent or advanced head and neck squamous cell carcinoma, such as methotrexate or a combination of 5-fluorouracil and cisplatin, are far beyond satisfaction. New chemotherapeutic agents, such as taxanes, paclitaxel and docetaxel, are among the most active drugs for head and neck cancer and a number of multidrug regimens containing a taxane and cisplatin have produced equivalent or higher response rates than conventional regimens. In addition, early clinical trials of novel molecular-targeted agents, such as epidermal growth factor receptors, tyrosine kinase inhibitors and gene targeted therapy, have shown encouraging results. Further clinical trials will be needed to optimally combine the biologic agents with chemotherapy and assess their effects on long-term control of cancer.