Fixation of mouse tissues for either histology or fluorescence microscopy is an essential first step in tissue preparation. In this protocol, we outline a reliable method for fixation and perfusion of mice for tissue histology or microscopy. Tissues prepared by this method can be used downstream as FFPE sections, cryosections for fluorescence microscopy, or tissue clearing for whole tissue imaging. For mice with transgenic fluorescent reporters, it is especially important that the tissues are preserved properly to ensure that the signal of the fluorescent reporter can be imaged.