This review provides an updated overview of mismatch repair (MMR) deficiency and microsatellite instability (MSI) in endometrial cancer (EC), focusing on the pathological assessment, interpretation, and reporting of MMR status. The review highlights the importance of immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6, and PMS2) as the gold standard for identifying MSI/MMRd EC, which accounts for about 30% of EC cases and has an intermediate prognosis. The review also discusses the clinical implications of MMRd EC, including its response to immunotherapy, particularly immune checkpoint inhibitors (ICIs). The text covers the molecular landscape of MSI/MMRd EC, the relationship between MMR deficiency and histological subtypes, and the challenges in interpreting IHC results. It emphasizes the need for a combined histo-molecular approach for risk stratification, incorporating molecular classification and histopathological features. The review concludes by addressing practical issues in IHC interpretation, such as poor fixation, cauterization artifacts, and the presence of lymphocytes and stromal cells, and provides guidelines for accurate assessment and reporting of MMR status in EC.This review provides an updated overview of mismatch repair (MMR) deficiency and microsatellite instability (MSI) in endometrial cancer (EC), focusing on the pathological assessment, interpretation, and reporting of MMR status. The review highlights the importance of immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6, and PMS2) as the gold standard for identifying MSI/MMRd EC, which accounts for about 30% of EC cases and has an intermediate prognosis. The review also discusses the clinical implications of MMRd EC, including its response to immunotherapy, particularly immune checkpoint inhibitors (ICIs). The text covers the molecular landscape of MSI/MMRd EC, the relationship between MMR deficiency and histological subtypes, and the challenges in interpreting IHC results. It emphasizes the need for a combined histo-molecular approach for risk stratification, incorporating molecular classification and histopathological features. The review concludes by addressing practical issues in IHC interpretation, such as poor fixation, cauterization artifacts, and the presence of lymphocytes and stromal cells, and provides guidelines for accurate assessment and reporting of MMR status in EC.