In 2006, more than 55 000 patients died of colorectal cancer in the US, accounting for ∼10% of all cancer deaths. Despite significant progress in screening combined with the development of novel effective therapies, colorectal cancer ranks second to lung cancer as a cause of cancer death. Twin studies indicate that 35% of all colorectal cancers are inherited, but high-penetrance tumor susceptibility genes only account for ∼3–6% of all cases. The remainder of the unexplained familial risk is presumably due to other high-penetrance genes, but polygenic mechanisms and low-penetrance tumor susceptibility genes are likely to account for a greater proportion of familial colorectal cancers. In this regard, there is growing evidence that a common hypomorphic variant of the type I TGF-β receptor, TGFBR1 *6A, may account for ∼3% of all colorectal cancer cases, a fraction higher than that attributable to mismatch repair genes MLH1 , MSH2 , MSH6 and PMS2 . Furthermore, TGFBR1 *6A is emerging as a potent modifier of colorectal cancer risk among individuals with a strong family of colorectal cancer. The TGF-β signaling pathway plays a central but paradoxical role in the predisposition and progression of colorectal cancer. TGF-β is a potent inhibitor of normal colonic epithelial cells acting as a tumor suppressor. However, TGF-β promotes the survival, invasion and metastasis of colorectal cancer cells, thereby acting as an oncogene. Understanding how selective alterations of the TGF-β signaling pathway contribute to colorectal cancer development and progression will likely permit the identification of an additional fraction of inherited colorectal cancer cases and provide novel opportunities for therapeutic intervention.