Hereditary nonpolyposis colorectal cancer (HNPCC) is the term given to a predisposition syndrome caused by inherited mutations in one of at least five DNA mismatch repair (MMR) genes. Dominant mutations in these genes predispose individuals to a range of cancers in addition to the most frequent, colorectal cancer. Endometrial cancer is the most notable additional malignancy, followed by ovarian, gastric, upper urethelial, and biliary cancers, and gliomas. Recognition of HNPCC is important so that targeted screening can be effected that will reduce the incidence of the main cancers. While such clinical criteria as Amsterdam and modified Amsterdam are reasonably specific, they lack sensitivity. Thus, tumor-related features have been used to improve sensitivity for identifying patients who can be selected for the relatively expensive direct mutation analysis of the various genes. Microsatellite instability (MSI) and loss of antibody staining for the proteins have been widely vaunted but have their own drawbacks. No one approach has received universal acceptance, and therefore adoption of one of perhaps three strategies, including clinical- and laboratory-based approaches, is still appropriate until an easier, quicker, and cheaper approach can be developed.