Optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) are new techniques that enable unprecedented high-resolution 3-D multimodal imaging of tissue structure and function. Applications include imaging macroscopic gene expression and microvasculature structure in unsectioned biological specimens up to 8 cm(3). A key requisite for these imaging techniques is effective sample preparation including optical clearing, which enables light transport through the sample while preserving the signal (either light absorbing stain or fluorescent proteins) in representative form. We review recent developments in optical-CT and optical-ECT, and compatible "fluorescence-friendly" optical clearing protocols.