The mismatch repair (MMR) system recognizes and corrects DNA bases misincorporation formed during replication and recombination, thus maintaining genome integrity. Alterations in the MMR complex due to germline/somatic mutations or methylation in the MMR genes can result in genome instability, which is a precondition for tumorigenesis and tumor progression. Therefore, MMR testing is becoming more and more relevant in oncologic pathology to help screen for hereditary cancer syndromes (i.e., Lynch syndrome), assess prognosis, and select patients eligible for immunotherapy with immune checkpoint inhibitors (ICIs). However, MMR as a biomarker has not been comprehensively characterized both in terms of diagnostic methodology and tailored guidelines, including companion and/or complementary diagnostic tests. This chapter provides an overview of the prognostic and predictive role of MMR status assessment across different tumor types and discusses the strengths and weaknesses of the available armamentarium for pathological testing.