Immunohistochemistry (IHC) and microsatellite instability (MSI) testing constitute the two major test modalities currently in use for detecting deficient mismatch repair (dMMR). Each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein IHC abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. Non-colorectal cases, and occasionally even colorectal tumors, that are MMR deficient by IHC but not MSI-high by current standards are being recognized. Recent data suggest that these immunohistochemistry abnormal/non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. In this episode, we discuss with Dr. Jinru Shia of Memorial Sloan Kettering Cancer Center her team's view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the dMMR test results.