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Gastroesophageal cancers continue to pose a significant health burden around the world. Advanced gastroesophageal cancer is an incurable condition and more research is desirable. Considerable new and important information, however, has become available.The number of phase III trials for patients with advanced gastroesophageal cancer is increasing and that is welcome news. Current results suggest that capecitabine can be substituted for 5-fluorouracil and oxaliplatin for cisplatin. Docetaxel, when combined with 5-fluorouracil and cisplatin, prolongs overall survival as well as improves safety, quality of life, and efficacy. S-1, a fourth generation oral fluoropyridine, is especially effective in combination with cisplatin. Dosing of S-1 is different between Western and Asian populations due to differences in metabolism by CYP2A6. Irinotecan should not be used as frontline therapy for advanced gastroesophageal cancer. Biologic agents are currently under investigation.Safer, more convenient, and more effective chemotherapy combinations are being developed for patients with advanced gastroesophageal cancer; however, considerable challenges exist to select the optimal therapy for an individual patient.