5-fluorouracil (5-FU) has been the mainstay of systemic therapy since its initial development 50 years ago for gastrointestinal cancer. In Japan, the development of orally administered fluoropyrimidines that maintain or improve the effectiveness of intravenous 5-FU, has been advanced. In the JCOG9912 trial, S-1 demonstrated significant non-inferiority to 5-FU. In the SPIRITS trial, S-1+CDDP combined chemotherapy showed significant statistical superiority to S-1 monotherapy. On the basis of these results, S-1+CDDP combination therapy was adopted as the standard cancer chemotherapy regimen for inoperable and recurrent gastric cancer. The ACTS-GC trial suggested that adjuvant chemotherapy with S-1 should be adopted as the standard treatment for stage II/III gastric cancer after curative D2 gastric dissection. This manuscript describes the clinical development of oral fluoropyrimidines (S-1, capecitabine) and their modulators for gastric cancer.