Patients with advanced squamous cell head and neck cancer have a dismal long-term survival rate not only because of metastatic disease, but also primarily because of failure in local disease control. The role of chemotherapy in recurrent or metastatic head and neck cancer has largely been palliative. Several chemotherapy agents, including docetaxel, paclitaxel, and ifosfamide, have been extensively studied, either alone or in combination regimens, for the treatment of recurrent or metastatic disease. These have resulted in response rates that are similar or higher than those obtained with the gold standard combination, cisplatin/ fluorouracil. Single-agent and combination studies of vinorelbine and gemcitabine have demonstrated modest activity in recurrent or metastatic disease. Phase III trials are planned that will compare taxane-based regimens with cisplatin and 5-fluorouracil in recurrent or metastatic head and neck cancer. Meanwhile, new drug and compound development, including monoclonal antagonists to the epidermal growth factor receptor, farnesyl transferase inhibitors, and oncolytic viruses are being tested in this setting.