Rigorous validation with ground truth information such as histology is needed to reliably assess the current and potential value of MRI techniques to characterize tissue and identify disease-related tissue alterations. Commonly used methods that aim to directly correlate histology and MRI data generally fall short of this goal due to spatial errors that preclude direct matching. Errors result from tissue deformation, differences in spatial resolution and slice thickness, non-coplanar and/or nonintersecting plane orientations, and different image contrast mechanisms. Some of these problems arise from limitations in standard protocols for clinical tissue processing and histology-based pathology reporting, and to some extent can be addressed by modifications to standard protocols without compromising the clinical process. Typical modifications include ex vivo specimen MRI, block-face photography, addition of fiducial markers, and 3D printed molds to constrain tissue deformation and guide sectioning. This review summarizes the advantages and limitations of MRI validation techniques based on coregistration of MRI with whole-mount histology of tissue specimens. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 1.