The utility of immunohistochemical detection of DNA mismatch repair (MMR) protein in screening colorectal tumors for hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been the focus of much intensive research over the last 10 years. Particular attention has been given to the relative usefulness of immunohistochemistry (IHC) versus testing of tumor microsatellite instability (MSI). Earlier work that focused on mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) has created a false impression that IHC has a lower sensitivity than MSI testing in predicting germline mutation. More recent studies that included postmeiotic segregation increased 2 (PMS2) and MSH6, on the other hand, have demonstrated an IHC predictive value that is virtually equivalent to that of MSI testing. Such added value of PMS2 and MSH6 can be explained by the biological and biochemical properties of the MMR proteins. On the premise that IHC with PMS2 and MSH6 is as sensitive as MSI testing, given that IHC is easily available and generally inexpensive and, importantly, identifies the affected gene, it is reasonable to regard IHC as a more optimal first-line screening tool than MSI testing for identifying HNPCC. MSI testing can provide a fallback position in equivocal situations, while remaining an important research tool. However, for IHC to be used as a first-line screening test requires that both pathologists and clinicians be aware that IHC results may be construed as "genetic information," and that appropriate procedures should be established to ensure patient understanding and consent.