The “International Workshop on Diagnostic Guidelines for Hereditary Non-Polyposis Colorectal Cancer and Microsatellite Instability” represents the third workshop in this series. In November 1996, NCI’s DCP convened a workshop entitled “Intersection of Pathology and Genetics in HNPCC Syndrome.” In December 1997, another workshop, “International Workshop on Microsatellite Instability and Replication Error Phenotypes in Cancer Detection and Familial Predisposition,” was sponsored by the NCI. Recommendations developed at these two workshops included the Bethesda Guidelines and panel of five specific microsatellite markers that have broad utility in several experimental and diagnostic settings. However, recent findings warranted a re-examination of the current guidelines for HNPCC diagnosis. MSI and immunohistochemistry (IHC) detection are other molecular tests that have been developed for detecting DNA mismatch repair (MMR) defects and were not included in previous HNPCC diagnostic guidelines. The “International Workshop on Diagnostic Guidelines for Hereditary Non-Polyposis Colorectal Cancer and Microsatellite Instability,” held in December 2002, brought together experts in the areas of hereditary nonpolyposis colorectal cancer (HNPCC) and microsatellite instability (MSI). Participants were charged with reviewing, evaluating, and updating existing criteria for HNPCC and MSI, as well as with providing recommendations to the NCI based on new insights into the disease and its manifestations. The workshop’s primary goal was to generate recommendations on appropriate strategies for: (1) evaluating MSI, (2) diagnosing HNPCC, and (3) identifying HNPCC mutation carriers. In applying the results of new research on HNPCC, workshop participants were asked to consider the previous recommendations for MSI testing, refined these recommendations, and identify the most effective screening approaches. First case of Lynch syndrome (HNPCC) may have been reported by Albert Warthin, who first suspected and documented the disorder in his affected seamstress (she died of endometrial cancer), in 1895. Dr. Warthin published the woman’s family history, characterized by a pattern of gynecologic cancer – specifically endometrial cancer – and many other gastrointestinal cancers. In 1961, Dr. Lynch documented a similar experience, with a patient whose family was riddled with colon and endometrial cancers. Dr. Lynch and colleagues subsequently identified other families with the same pattern of cancers, noting that in addition to colon and endometrial cancers, gastric, small bowel, and other cancers occurred significantly more often in these families [1– 4]. It was observed that there was a significantly marked 70–80% excess of proximal colon cancers in these patients. Cutaneous manifestations such as Muir Torre features [5,6], sebaceous adenomas, and sebaceous carcinomas also were found to be associated with the disorder. Aside from colorectal cancers (CRC), endometrial cancers were identified as the second-leading cancer associated with the syndrome. With current detection and treatment options, it is felt that no one with HNPCC should die from colorectal cancer, assuming that the patient has been identified, has a dedicated physician, and has been referred to a gastroenterologist