Colorectal cancer (CRC) is a major public health concern, ranking among the leading causes of cancer death in both men and women. Because of this continued burden there is a clear need for improved treatment, and more importantly prevention of this disease. In recent years there is significant evidence to support the hypothesis that guanylyl cyclase C (GCY2C) is a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor is an important step in the disease process. Thus, ligand replacement therapy has been proposed as a strategy to prevent CRC. Until recently this strategy was not clinically plausible; however, the recent regulatory approval of linaclotide (LINZESSTM, Forest Laboratories and Ironwood Pharmaceuticals, Inc.), an oral GUCY2C ligand, has raised the possibility of utilizing this strategy clinically to prevent CRC.