Cancers of the esophagus, stomach and pancreas constitute a major cause of cancer death worldwide. Despite improvements in both surgical techniques and chemotherapy regimens these tumors remain a great therapeutic challenge and most patients still die of their disease, even after apparent 'curative resection'. There is a clear need for more effective treatments, particularly for patients with advanced disease, since this is the most common presenting stage. In this review we will discuss the clinical strategies in use and identify the best current treatment options based on randomized clinical trial data. Novel strategies under investigation are discussed and speculation made as to which will be standard treatments of the future.