Endoscopy altered the practice of gastroenterology by providing nonoperative access to the gastrointestinal (GI) tract and the pancreaticobiliary system. The detection of microscopic and biochemical changes within the mucosa and submucosa, however, has remained beyond the realm of routine endoscopy. Distinguishing hyperplastic from neoplastic polyps, differentiating malignant from benign ulcers, and detecting mucosal dysplasia in patients with inflammatory bowel disease or Barrett’s esophagus (BE) remains within the purview of the GI pathologist. In particular, endoscopic detection of dysplasia relies on the recognition of visible lesions (e.g., adenomatous polyps, dysplasia-associated lesion, or mass), or random sampling of tissue (biopsy). Endoscopy alone can neither reliably detect regions of invisible or flat dysplasia nor distinguish dysplasia from nondysplastic changes within visible lesions. Histological examination of the excised material is required to diagnose and locate dysplasia. Random biopsy techniques are subject to sampling errors and increased risk because of long procedure time and multiple biopsy sites. In patients with inflammatory bowel disease, it has been estimated that a total of 33 and 56 biopsy specimens are required for a 90 and 95% confidence to detect dysplasia or carcinoma (1).