For palliation of patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC), the major classes of commonly used cytotoxic chemotherapeutic agents are platinum agents (cisplatin, carboplatin), taxanes (paclitaxel, docetaxel), and antimetabolic agents (methotrexate, 5-fluorouracil). Cetuximab, a monoclonal antibody directed against the extracellular domain of the epidermal growth factor receptor, also shows modest activity against R/M HNSCC. Because the overall management of patients with R/M HNSCC often involves multidisciplinary input, this review focuses on data that help guide decision-making in scenarios in which palliative chemotherapy is planned. Avenues for ongoing research are also presented.