Distinguishing dysplastic (adenomatous) from nondysplastic (hyperplastic) polyps is not possible using standard endoscopic techniques. Routine endoscopy is also unable to identify regions of flat dysplasia in ulcerative colitis or Barrett's esophagus. Endoscopists depend on histology to characterize these lesions, which introduces additional costs and risks and invariably delays patient management. A new series of technologies, collectively termed optical biopsy, are capable of immediate, noninvasive diagnosis of dysplasia. We shall review the 2 most promising of these technologies, namely laser-induced fluorescence (LIF) and light-scattering spectroscopy (LSS). The principle of LIF is that dysplastic cells emit light (fluoresce) differently than cells that are not dysplastic. Dysplastic cells may contain compounds capable of causing fluorescence (fluorophores), which are different from those found in nondysplastic cells or compounds which are similar but found in an abnormal concentration compared to nondysplastic cells. When a laser or filtered light is used to illuminate the intestinal mucosa, dysplastic cells give off a characteristic fluorescence that can be detected with fiber optic probes or, more recently, standard charged-coupled device (video) chips in the endoscope. Previous studies have evaluated light sources and specific wavelengths of light that optimally cause fluorescence. In addition, the fluorescence characteristics of gastrointestinal tissue are currently being assessed to determine which are best capable of distinguishing dysplastic from nondysplastic lesions. Overall, LIF is very accurate, with sensitivity and specificity of greater than 90%. However, it is less accurate in identifying low-grade, nonpolypoid dysplasia. LSS is based in part on the principle that small particles can be characterized by the way in which they scatter light. When used to study the superficial mucosa of patients with Barrett's esophagus, light-scattering spectroscopy can determine the size and number of nuclei. Because dysplastic cells develop abnormally large nuclei with a larger number of nuclei per area (“crowding”) than nondysplastic tissue, LSS may be able to aid in the endoscopic detection of dysplasia. Recent studies in patients with Barrett's esophagus have shown that LSS is capable of accurately detecting both low-grade and high-grade dysplasia. Importantly, because these techniques use objective parameters such as nuclear size and number, they may be less subject to the interobserver variation seen in histological interpretation of dysplasia. New techniques such as LIF and LSS have the potential to provide immediate, noninvasive tissue diagnoses that can accurately distinguish nondysplastic from dysplastic polyps and may be useful for localizing areas of nonpolypoid dysplasia in patients with ulcerative colitis or Barrett's esophagus.