Subepithelial tumors (SETs) are occasionally found in the esophagus and stomach during upper endoscopy. Most SETs are asymptomatic and therefore clinically insignificant. However, SETs do have malignant potential, and therefore it is important to distinguish malignant from benign lesions. Among gastric SETs, gastrointestinal stromal cell tumors (GISTs) have malignant potentials that are related to tumor size; however, malignancy can occasionally be found in smaller lesions. Endoscopic ultrasound (EUS) can be used to diagnose GISTs preoperatively, although differential diagnosis on the basis of imaging alone is insufficient. However, when used in combination with EUS-guided fine needle aspiration, diagnostic accuracy increases, although the results can be quite variable. Therefore, we performed endoscopic biopsy of gastric SETs using the endoscopic submucosal dissection (ESD) technique. Our data indicate that deep biopsy via ESD is a safe modality of high diagnostic yield compared with EUS-guided fine needle aspiration in determining the histopathologic features of upper gastrointestinal (GI) SETs, relatively. In addition, pathologic confirmation can be more important than EUS finding. Diagnostic results improve clinical decision making on managing upper GI SETs. It can be recommended that this modality should be considered in upper GI SETs before determining whether tumors should undergo (Fig. 1).