While cancers of the upper gastrointestinal tract are related by location, they have distinct clinical and molecular characteristics. This review will focus on the molecular biology of esophageal adenocarcinoma (EAC) of which alterations in p53, overexpression of cyclin D1, loss of p16, and aneuploidy have been best characterized. Key similarities and differences, when compared to esophageal squamous cell carcinoma (ESCC), gastric adenocarcinoma (GC), and adenocarcinoma of the gastric cardia (AGC), will also be highlighted. Currently, malignancies of the upper gastrointestinal tract are often diagnosed at an advanced stage and are generally associated with a poor patient prognosis. With an improved understanding of the molecular biology of these tumors, there is hope that new targets for diagnosis, chemoprevention, and therapy will be developed.