Our work on theoretical, experimental, and computational aspects of light -tissue interactions for non-invasive quantitative optical imaging and spectroscopy has been continued. Several new sets of time resolved transillumination of human breast patients have been provided by researchers at PTB in Berlin time of flight measurements in transillumination geometry of breast images in two wavelengths (670 and 780nm). We have applied our methodology known as time-dependent contrast functions, to quantify the size and the optical properties of the normal tissue background and those of the tumor localized by standard mammography. We were successfully able to find the exact location, estimate the size, and retrieve the scattering and the absorption coefficients of the tumor(s) and those of the background(s). Separation of the scattering and absorption properties allowed us to use standard spectroscopic techniques to estimate the oxygen saturation and the total blood volume of the tumor(s) and background tissue(s. Effects of breast edges on measured light intensities have been modeled using the mean time of flight which depends on the distance of the laser source and the boundaries of the breast. In order to avoid incisional biopsy in the oral cavity, a theoretical framework has been developed to quantify the thickening of the epithelial layer in oral mucosa non-invasively. We have used our oblique angle spectroscopic device on seven patients with oral leukoplakia in a double-blinded Phase II clinical trial (designed by NCI) for the study of inflammation and effects of chemopreventative drugs. As the results of the clinical trial will be available. we will compare our finding with results of punch biopsies. This allow us to evaluate the robustness of our method, and refine our theoretical model and the design of our device. We are pursuing the use of exogenous and endogenous fluorescent markers to be able to achieve specificity of the spectroscopic signatures of the tissue abnormality under investigation. In collaboration with the Tel-Aviv University we continue our research on practical implementation of our previously developed 3D reconstruction algorithm which localizes the position and the concentration of fluorophore masses. Our inverse algorithm will be used to find the position and the concentration of liposomes filled with fluorescent particles as a model for localized fluorescent masses in vivo. Mice models have been successfully used to assess the robustness of our model. Along these line of research, we are testing an analytical theory of photon migration to retrieve the life-time of biological analytes by using phantom experiments. We are continuing a collaboration with researchers at NCI to study the practical use of our photon migration theory in the development of a guided biopsy infrared fluorescence imaging system for sentinel node detection in breast cancer using fluorescent particles.