Advanced squamous carcinoma of the upper aerodigestive tract continues to be a therapeutic challenge. With recent advances in chemotherapy, systemic treatment has been used in an attempt to improve treatment results produced by radiation therapy and/or surgery. Such multidisciplinary experimental approaches have given new hope for cure in stage III and stage IV disease, but have reopened old questions as to the natural history and underlying biology of this disease. Multidisciplinary treatment, whether synchronous or sequential, appears to improve survival for stage III and stage IV patients achieving a complete response to chemotherapy plus irradiation. The role of surgery or radiotherapy for control of primary or nodal disease remains unchanged and is an essential component of all curative treatment plans.