Upper gastrointestinal tumors involving the esophagus and the stomach are a serious public health problem worldwide. The West has seen a dramatic increase in the incidence of gastroesophageal cancers in the past 2 decades. Although Barrett esophagus has been well characterized, the exact pathway to developing frank malignancy remains undefined. Current treatments for locoregional disease include surgery, chemotherapy, radiation therapy, or some combination thereof. Clinical trials are currently investigating biologic agents that target signaling pathways in carcinogenesis. Whether this research translates into an improved therapeutic index remains to be seen. This review provides a comprehensive update to physicians and residents who contribute to the care of these patients. Studies in the English language were identified searching PubMed (January 1, 1980, through February 29, 2008) using the terms esophagus, gastric, carcinoma, adenocarcinoma, squamous cell, radiation, chemotherapy, surgery, esophagectomy, and targeted therapy.