High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.