Recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) are difficult problems and likely to become more challenging as concurrent chemotherapy and radiation are more widely used. Randomized studies reported in 1992 established the combination of cisplatin and infusional 5-fluorouracil (5-FU) as the reference regimen for chemotherapy-naive, good-performance status patients. Subsequently, a randomized study of 194 patients comparing cisplatin and 5-FU to cisplatin and paclitaxel found better tolerance, better pain relief, and improved quality of life with the newer regimen, but no survival differences (medians of 9 months) were detected. Phase II studies of a platinum/taxane combination with a third drug have reported response rates of greater than 50%, including 15% complete responses. A number of non-platinum-containing regimens are active in pretreated patients. Gefitinib has shown median survival times comparable to those achieved with cisplatin and paclitaxel, and appears especially promising for patients who recur after cytotoxic chemotherapy. Newer antifolates, agents that target or restore deficient p53, and other signal transduction inhibitors are under study. © 2004 Elsevier Inc. All rights reserved.