Available evidence supports the existence of two major pathways of neoplastic development in the gastroesophageal region: the Barrett pathway, related to gastroesophageal reflux disease, and the gastric pathway, related to Helicobacter pylori infection. The existence of an independent junctional pathway is questionable, and gastroesophageal junction adenocarcinomas share features of esophageal and gastric adenocarcinomas. It has been impossible to accommodate all data that are provided by different levels and tools of observation in tumors that develop in the gastroesophageal region in a single, coherent classification. That is why the stratification of pathologic risk in such tumors, and their respective precursors, incorporates features from topography, histology, immunohistochemistry, and molecular pathology.