Two pivotal phase II studies of S-1 in advanced gastric cancer showed response rates of 44% and 49%, and the overall survival time was 207 and 250 days, respectively. The response rate of S-1 exceeded the response rates of other approved drugs, and was comparable to that of combination chemotherapies such as 5-fluorouracil (5-FU) plus cisplatin (CDDP). These data suggested that S-1 could be used as a first-line drug for gastric cancer with a great advantage in quality of life (QOL), because it is an oral drug and can be used at an outpatient clinic. The overall incidences of adverse reactions in the phase II studies were 74.3%, and that of grade 3 or worse were 14.9%. The main adverse reactions were myelosuppression and GI toxicities. As hematological toxicity was more common than other oral fluoropyrimidine derivatives such as UFT, a careful hematological monitoring is necessary. To confirm the survival benefit of S-1 in advanced gastric cancer, a phase III trial of S-1 vs 5-FU vs CDDP plus irinotecan (CPT-11) has been conducted by the Japan Clinical Oncology Group (JCOG), and these results have been awaited. Furthermore, the combination of S-1 with CDDP, CPT-11 or taxane for the treatment of gastric cancer is feasible and active, and phase III studies of S-1 vs several combination therapies including S-1 are also in progress. The effect of S-1 in adjuvant setting is also promising. Currently, a phase III study of surgery alone vs S-1 in patients with a curative resection of gastric cancer has been developed. Further therapeutic benefits are also expected by combining S-1 with other chemotherapeutic agents such as molecular targeted agents.