One of the earliest references to heredity in colorectal cancer dates to Aldred Warthin's now-famous recollection of his seamstress' distress regarding "cancer excess" in her family history. Her prediction of an early demise secondary to cancer of the female organs, colon, or stomach proved true. The slow, arduous investigation that ensued followed a tortuous route of nearly eight decades before the implications of such family histories were widely acknowledged through the designation of hereditary nonpolyposis colorectal cancer or Lynch Syndrome Variants I and II. The story of hereditary nonpolyposis colorectal cancer is one of chance meetings, the selfless sharing of information, perseverance in the face of adversity, meticulous scientific documentation, and ultimate vindication by a scientific process that yielded molecular genetic evidence through the identification of the culprit mutations (hMSH2, hMLH1, hPMS2, and hMSH6). Our purpose is to provide a brief outline of the course charted by the study of the genetics of hereditary nonpolyposis colorectal cancer. This should be of particular interest to the readers of this Journal as we celebrate 100 years of dedication to the diagnosis and treatment of diseases of the colon, rectum, and anus through the efforts of The American Society of Colon and Rectal Surgeons.