Transforming growth factor (TGF)-beta is a naturally occurring potent inhibitor of cell growth. TGF-beta binds first to a Type II (TGFBR2), then a Type I receptor (TGFBR1). TGFBR1 activation results in the phosphorylation of intracellular messengers, the SMADs. Unrestricted cell growth due to decreased growth inhibitory activity is a paramount feature of a defect in TGF-beta function. There is growing evidence that common variants of the TGF-beta pathway ligand and receptors that alter TGF-beta signaling modify cancer risk. Approximately 14% of the general population carry TGFBR1*6A, a variant of the TGFBR1 gene that results in decreased TGF-beta-mediated growth inhibition. Recent studies show that overall cancer risk is increased by 70 and 19% among TGFBR1*6A homozygotes and heterozygotes, respectively. This suggests that TGFBR1*6A may contribute to the development of a large proportion of common forms of cancer and may become a target for cancer chemoprevention. While decreased TGF-beta signaling increases cancer risk, TGF-beta secretion and activated TGF-beta signaling enhances the aggressiveness of several types of tumors. The activated TGF-beta signaling pathway is emerging as an attractive target in cancer and the authors predict that assessment of functionally relevant variants of this pathway will lead to the identification of individuals with a higher cancer risk and account for some forms of familial cancer susceptibility. In addition, it is predicted that inhibitors of the TGF-beta signaling pathway will find their way into cancer clinical trials, leading to delays in tumor progression and improvements in overall survival.