The increasing availability of powerful fluorescent agents for reporting on functional and molecular tissue processes in-vivo opens new ways for detecting disease, characterizing cellular and sub-cellular processes and for assessing the effects of treatments. With this increased capacity for visualization conies a pressing need for highly advanced imaging technology that can accurately resolve in three dimensions and quantify the bio-distribution of such fluorochromes through dense tissues. Fluorescence macroscopy of entire animals and tissues is a most challenging and still largely unexplored field of imaging sciences, whose full potential is far from being reached. This proposal offers to develop a hybrid FMT system that combines the most advanced current developments on optical tomography with high-resolution X-ray Computed Tomography to offer unprecedented imaging capacity for small animal imaging. The system proposed is a fundamentally new design that assumes complete projection (360 degrees) illumination and detection, similarly to geometrical practices seen in X-ray CT. A CCD camera is used for obtaining high spatial sampling photon collection in the absence of previously utilized matching fluids or fibers in physical contact with tissue. As such, the proposed design and methods are not simply an incremental step forward compared to previous implementations but offer a new generation in terms of performance and experimental simplicity. While we expect the technology to find many small animal imaging applications, we are particularly interested in applying it for improving imaging in mouse models of cancer. We hypothesize that the proposed developments will yield a practical and highly efficient system that can become a method of choice in many preclinical studies involving in-vivo imaging of entire animals.