Approximately 5% of the 140,000 cases of colorectal cancer diagnosed annually are attributable to an underlying hereditary colorectal cancer syndrome. However, this is likely to be an underestimation. Our understanding of the genetic basis, as well as the guidelines for clinical management of these syndromes, continue to evolve rapidly. Because of the high risk of not only colorectal cancer but also multiple extracolonic tumors, it is crucial for clinicians to recognize the unique features in the diagnosis and management of these high-penetrance syndromes, including familial adenomatous polyposis, MYH-associated polyposis, and hereditary nonpolyposis colon cancer.