Considerable progress has been made in the development of more effective chemotherapy regimens for squamous cell head and neck carcinomas. Unfortunately, increased response rates have not been translated into marked improvements in survival since durations of response have been brief, and the natural history of the disease has ultimately remained unaltered. Since the development of drug resistance is a major obstacle to successful antineoplastic chemotherapy, comprehensive efforts have been focused on understanding the underlying mechanisms. In this review, general and specific aspects of drug resistance related to head and neck cancer are addressed. In particular, mechanisms of resistance towards the most widely used antineoplastic drugs in head and neck malignancies--methotrexate, cisplatin, 5-fluorouracil, bleomycin, and vincristine--are discussed.