Most head and neck carcinomas are squamous cell carcinomas (HNSCCs). The combination of cisplatin with a continuous infusion of 5-fluorouracil (5-FU) has been a standard chemotherapy regimen for HNSCC. Based on basic and clinical studies, the critical plasma concentration of 5-FU is suspected to be about 0.1 microg/ml. The administration of the conventional dose of S-1 including dihydropyrimidine dehydrogenase (DPD), an metabolic inhibitor of 5-FU, results in exceeding the critical plasma concentration of 5-FU, and the long-term administration with high plasma concentration of 5-FU is considered to show clinical effectiveness in head and neck cancer. The results of early and late phase II studies on head and neck carcinoma were also described in the present paper.