Colorectal cancer is a major cause of morbidity and mortality among types of cancer in the United States. Significant progress has been made in understanding the molecular mechanisms that lead to it. Much knowledge was obtained through study of genetic changes that occur in individuals with a familial predisposition to colorectal cancer, including familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) syndromes. The gene with mutations that result in FAP has been identified as adenomatous polyposis coli (APC). Similarly, mutations in several genes that normally function in DNA mismatch repair result in HNPCC. Colorectal cancer is the result of accumulated mutations in several additional oncogenes or tumor suppressor genes, and this information leads to the formulation of a genetic model for the disease. Recent studies have also identified a relatively prevalent polymorphism in the APC gene in Ashkenazi Jews that is associated with an increased risk for colorectal cancer. These studies present a paradigm based on the APC mutation (APC I1307K) for the screening of cancer susceptibility genes in the population at large. Currently available techniques for genetic testing of colorectal cancer are also discussed in this review, along with their ethical implications.