Multi-fluorescent High Resolution Episcopic Microscopy (MF-HREM) is a serial-sectioning, block-facing, wide-field fluorescence technique. It can image large volumes (>0.5mm3) at high resolution (~2um) without the need for tissue clearing or optical sectioning. We detail developments in sample processing including stain penetration, resin embedding and imaging. In addition, we describe image post-processing methods needed to segment and further quantify these data. Finally, we demonstrate the wide applicability of MF-HREM by: 1) quantifying adult mouse glomeruli. 2)...