Endoscopic submucosal dissection (ESD) is a novel endoscopic procedure first developed in the 1990s which enables en bloc resection of gastric neoplastic lesions that are difficult to resect via conventional endoscopic mucosal resection. However, given that ESD increases the risk of intra- and post-ESD delayed bleeding and that platelet aggregation and coagulation in artificial ulcers after ESD strongly depend on intragastric pH, faster and stronger acid inhibition via proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2RAs) as well as endoscopic hemostasis by thermocoagulation during ESD have been used to prevent ESD-related bleeding. Because PPIs more potently inhibit acid secretion than H2RAs, they are often the first-line drugs employed in ESD treatment. However, acid inhibition after the initial infusion of a PPI is weaker in the early phase than that achievable with H2RAs; further, PPI effectiveness can vary depending on genetic differences in CYP2C19. Therefore, optimal acid inhibition may require tailored treatment based on CYP2C19 genotype when ESD is performed, with a concomitant infusion of PPI and H2RA possibly most effective for patients with the rapid metabolizer CYP2C19 genotype, while PPI alone may be sufficient for those with the intermediate or poor metabolizer genotypes.