Since the development of monoclonal antibodies against the MSH2 protein by Leach et al. in 1996, a series of investigations has been undertaken to determine the utility of immunohistochemical detection of DNA mismatch repair (MMR) gene proteins in the identification of hereditary or sporadic colorectal tumors with microsatellite instability. These studies, however, have been performed with different aims and on different patient populations. Interpretation of these immunohistochemical data relies on a thorough understanding of the biological and technical factors that affect the detection of MMR proteins. In this review, we analyze the data from the published research studies, pointing out the various factors affecting immunohistochemical detection of MMR proteins and projecting the utility of immunohistochemistry in different clinical settings.