Combined modality programs that were developed over the past two decades demonstrated that the nonsurgical therapy of locoregionally advanced head and neck cancer is feasible and produces survival outcomes that are at least comparable with surgery. The systemic therapy of head and neck cancer has gained momentum in recent years. Several randomized studies have shown that the concurrent administration of chemotherapy and radiation therapy is superior to radiation therapy alone. In consecutive clinical studies since 1986, we have developed multiagent chemoradiotherapy regimens based on initial observations with the 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy combination. Three consecutive multicenter phase II trials reported that the combination of 5-FU and hydroxyurea with either cisplatin or paclitaxel along with twice daily radiation therapy administered every other week is a highly effective regimen with local control rates that approach 90% and 3-year survival rates of approximately 60% in patients with stage IV disease. The vast majority of patients in these studies achieved anatomical organ preservation. A reversal of the historical pattern of failure was evident, with distant sites becoming the predominant site of failure in each trial. The paclitaxel-containing regimen was better tolerated than the cisplatin-containing regimen and was advanced to further clinical testing. The incorporation of induction chemotherapy may improve the results of treatment by targeting systemic micrometastatic disease.