S-1 is an oral 5-fluorouracil(5-FU) prodrug,which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase,the key enzyme of 5-FU catabolism.Recently,two important studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan.In the first study(GEST study),S-1 demonstrated non-inferiority to gemcitabine(GEM) in overall survival(OS) for metastatic or locally advanced pancreatic cancer,but combination chemotherapy with GEM and S-1 did not show superiority to GEM in OS.In the second study(JASPAC-01 study),S-1 showed superiority to adjuvant chemotherapy with GEM in OS in patients with resected pancreatic cancer.In addition to GEM,S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan.To date,many studies have investigated the effectiveness of S-1 in various settings,such as first-line chemotherapy for metastatic or locally advanced pancreatic cancer,second-line chemotherapy after GEM failure,and chemoradiotherapy for locally advanced disease.In this review,we focus on recent clinical trials of S-1-based chemotherapy for advanced pancreatic cancer. S-1 is an oral 5-fluorouracil (5-FU) prodrug, which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase, the key enzyme of 5-FU catabolism. Published, two important studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study (GEST study), S-1 demonstrated non-inferiority to gemcitabine (GEM) in overall survival (OS) for metastatic or locally advanced pancreatic cancer, but combination chemotherapy with GEM and S-1 did not show superiority to GEM in OS. the second study (JASPAC-01 study), S-1 showed superior to adjuvant chemotherapy with GEM in OS in patients with resected pancreatic cancer. addition to GEM, S-1 is now considered as the key drug in the management of pancreatic cancer in Japan. To date, many studies have investigated the effectiveness of S-1 in various settings, such as first-line chemotherapy for metastatic or locally advanced pancreatic cancer, second-line chemotherapy after GEM failure, an d chemoradiotherapy for locally advanced disease. In this review, we focus on recent clinical trials of S-1-based chemotherapy for advanced pancreatic cancer.