Recent therapeutic developments that have provided new promising and successful approaches to the treatment of solid tumors are in large part due to the increasing understanding of their molecular biology. Despite this progress, these new therapies have provided minimal benefit in the treatment of upper gastrointestinal (GI) malignancies. Hence, the overall survival of patients with upper GI tumors remains dismal. These disappointing results are largely due to the lack of early detection strategies, inadequate medical treatments and the poor understanding of upper GI tumor biology. Clinically, the treatment paradigm has been evolving for these malignancies. Esophageal cancer is now commonly treated with preoperative chemoradiation in the USA, in both academic and community cancer centers, due to its theoretical advantages. Adjuvant chemotherapy and chemoradiation are also frequently used in patients with pancreatic cancer. Exciting prospects remain in the medical and surgical treatment of these malignancies with the inclusion of biologic agents in many protocols, newer chemotherapeutic agents (such as S-1 in the treatment of gastric cancer), and the use of minimally invasive procedures for the treatment of premalignant and, possibly, early malignant lesions of the esophagus and stomach. This review focuses on the current practice in the management of upper GI tumors and summarizes the recent advances in the field.