A role for chemotherapy in the multidisciplinary treatment of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) is yet to be defined. Results of uncontrolled studies indicate high response rates to induction chemotherapy and an association between a response to chemotherapy and either local-regional control or survival. Unfortunately, results of randomized, controlled trials have not confirmed an overall survival advantage with such treatment. From 1979 to the present, the Dana-Farber Cancer Institute has registered more than 224 patients on two trials of induction and adjuvant chemotherapy for patients with stage III to IV SCCHN. Protocol 80-016 (1979 to 1983) evaluated two cycles of induction cisplatin, bleomycin, and methotrexate/leucovorin (PBM) before local regional treatment in 114 patients. Eighty-nine (78%) patients responded to PBM, with 30 (28%) patients achieving a complete response (CR). After surgery and/or radiotherapy (RT), 46 responders to induction PBM entered a trial of the randomly assigned additional adjuvant PBM. Protocol 83-084 (1983 to present) randomly assigned patients to receive up to four cycles of either induction PBM or cisplatin and infusion 5-fluorouracil before local treatment. Adjuvant chemotherapy was not used in the latter study. Updated results from both trials will be presented, with their implications for future phase II and III multidisciplinary studies. Optimal approaches to the treatment of patients with advanced SCCHN can include planned reductions in the extent of surgery or RT offered to selected patients with a good response to induction chemotherapy but may require adjuvant chemotherapy for patients at high risk for recurrent disease. Until the rate of CR to induction chemotherapy is reproducibly over 50%, documentation of an improved overall survival with multidisciplinary treatment may be difficult.