Intrinsic fluorescence, diffuse reflectance, and light-scattering spectroscopy provide complementary information on biochemical and morphologic information extending potentially from the molecular to the tissue level. Model-based spectral analysis in each case yields results about specific tissue parameters in a quantitative manner.Preliminary studies demonstrate that these parameters can be used for the development of algorithms that can detect dysplastic changes in patients with Barrett's esophagus (BE) with high sensitivity and specificity. Studies validating tri-modal spectroscopy based algorithms and real-time spectroscopic data analysis are under way to provide a more accurate and extensive assessment of the potential of this approach as a clinical noninvasive tool that could improve the management and treatment of BE dysplasia.