Cancers of the upper gastrointestinal tract include cancers of the esophagus, gastroesophageal junction, and stomach. Metastatic or unresectable upper gastrointestinal malignancies are incurable but do benefit from palliative chemotherapy. Several agents have been examined in the treatment of these diseases, with modest single-agent activity. In combination, these chemotherapeutic agents demonstrate improved antitumor activity with acceptable toxicity. Several combination therapies have been developed and have been examined in recent large phase III randomized clinical trials. These studies, for the most part, have failed to demonstrate a survival advantage over the reference arm. However, with the examination of newer cytotoxic agents, as well as with the application of molecularly targeted approaches to upper gastrointestinal malignancies, there remains hope for improved therapies for these diseases in the future.