Despite the progress in treatment protocols, gastric cancer remains a challenging disease. Systemic chemotherapy is of crucial importance for patients with metastatic or recurrent disease, and new developments in chemotherapy regimens have been seen in recent years. An oral 5-fluororacil (5-FU) agent, S-1, is emerging, with promising results. Various S-1 combination regimens, mostly with cisplatin, are being examined extensively, and the combination of S-1 with oxaliplatin is the focus of recent studies. In this study, phase I/II studies of combination chemotherapy with S-1 and platinum in patients with metastatic or recurrent gastric cancer were reviewed. We found that the combination of S-1 plus cisplatin was highly active against advanced gastric cancer, with a favorable toxicity profile. The response rates were 53%-74% in Japan, 47.6% in Korea, and 51% in the United States and Europe. There is no internationally accepted standard care for patients with advanced gastric cancer yet, but S-1 is likely to replace infusional 5-FU, and oxaliplatin may represent an alternative to cisplatin in the near future. More innovative therapies, particularly with molecular-targeted drugs, are needed to meet the needs of patients in the era of tailored medicine.