Gastric cancer is the fourth most common malignancy worldwide with Japan, Korea, Taiwan, China, Mongolia and many countries in South America and eastern Europe, as well as parts of the Middle East, contributing to the majority of cases. In the USA, it was estimated that approximately 10,620 deaths would be caused by gastric cancer in 2010. Gastric cancer is often diagnosed in its advanced stages. Current first-line treatment for advanced gastric cancer (AGC) using triplet combination chemotherapy containing a platinum-based compound, a fluoropyrimidine with an anthracycline (frequently added in Europe) or a taxane (more often used in the USA and elsewhere) has resulted in higher response rates and modest improvement in overall survival compared with doublet combinations. However, triplet combinations can be associated with increased toxicity compared with the doublets and patient selection becomes important. A desirable research strategy is to improve outcomes of patients with AGC by identifying treatments that are effective, convenient and safe. The interest in oral agents compared with intravenous agents is mounting. One oral fluoropyrimidine, S-1, is novel as it combines tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 is approved in Japan, China, Taiwan, Korea and Singapore for the treatment of patients with gastric cancer, and more recently has been approved in 27 European countries to treat AGC. Initial clinical trials in the USA and Europe observed diarrhea as the dose-limiting toxicity; however, initial Japanese studies reported myelosuppression as the dose-limiting toxicity. The differing dose tolerance in these two populations is likely due to polymorphisms in the CYP2A6 gene. Based on our review of Phase II and III studies, we conclude that S-1 is a convenient oral fluoropyrimidine that provides safety advantage over intravenous fluorouracil without compromising efficacy against AGC.