Identification of microsatellite instability (MSI) in colorectal cancer (CRC) patients can have prognostic, therapeutic, and family planning implications. MSI is a term that describes a shift in the length of microsatellite repeats because of mismatch repair gene deficiency secondary either to DNA methylation or genetic mutation. MSI testing is frequently performed on patients with suspected hereditary nonpolyposis CRC, and MSI is found in CRC samples from patients who eventually go on to be genotyped and confirmed to have Lynch syndrome. Other indications for MSI testing include prognosis determination, since MSI cancer patients do better than those with microsatellite stable cancers, and for chemotherapy selection, where some data indicate the lack of benefit to patients with microsatellite unstable CRCs treated with 5-Fluorouracil. During the histologic review of either a biopsy or a resection specimen, a pathologist's increased familiarity with the revised Bethesda criteria and awareness of the histopathological features commonly seen in colorectal tumors harboring MSI can increase the rate of clinically appropriate testing and improve patient care. Molecular analysis for MSI is performed routinely by a number of clinical laboratories on formalin-fixed paraffin-embedded tissue. Immunohistochemical stains can also be performed to assess for the absence of mismatch repair protein in a tumor cell. A representative case will be detailed to review the histology and the molecular data commonly observed in CRC showing MSI.