In recent decades there have been significant advances in our understanding of the genes that underlie hereditary susceptibility to colorectal cancer (CRC). In 2007 it is well established that mutations in DNA repair genes (MLH1, MSH2, MSH6, MYH) and Wnt pathway signal transduction inhibitors (APC) underlie a significant percentage of hereditary CRC susceptibility. However, it also is clear that the known CRC susceptibility genes do not explain fully the inherited risk seen even in families meeting the revised Bethesda guidelines. Furthermore, the optimal medical management of these syndromes is still being defined. What underlies CRC susceptibility in these highly unusual families that do not have identifiable mutations in the known genes, often referred to as syndrome X? This review addresses this important question that is relevant to our current understanding of the management of individuals with hereditary predisposition to CRC.