Although progress in the treatment of patients with colorectal cancer (CRC) has resulted in improved median survival, most patients with metastatic CRC still die of their disease, and essentially all patients with early-stage disease must undergo surgical resection and subsequently face the possibility of adjuvant chemotherapy. As effective screening and prevention strategies for CRC have been developed, identification of individuals with a hereditary predisposition to developing CRC is especially important and provides the opportunity to reduce disease burden in this high-risk population. Increased awareness and improved diagnostic techniques for hereditary CRC syndromes have facilitated more frequent diagnosis and management of a small number of highly penetrant syndromes within families. However, known high-penetrance genetic predisposition syndromes account for a minority of all familial CRC, leaving much of the genetic basis of CRC unexplained. Recent advances in high-throughput genotyping have made possible genome-wide association studies, which have identified novel genetic variants associated with modest increases in CRC risk. While these associations have helped to identify potentially important pathways in CRC carcinogenesis, at the current time, the clinical use of such genetic risk variants in colon cancer risk stratification remains limited.