Intestinal epithelium undergoes self-renewing cycles along the crypt-villus axis regulated by an array of distinct and opposing forces, which integrate to maintain intestinal homeostasis. An imbalance of these processes results in intestinal pathology. Indeed, a disruption of the equilibrium between proliferation of progenitor cells in the crypt and loss of senescent cells at the lumenal surface may be one mechanism contributing to the development of colon cancer. GC-C appears to play a central role in regulating proliferation and differentiation along the crypt-to-villus-axis. GC-C is expressed exclusively on the apical membranes of differentiated intestinal epithelial cells and is expressed along a crypt-to-villus gradient in intestine, with the greatest expression in the mild-villus where enterocytes transition from proliferation to differentiation. GC-C expression is regulated by the CDX2 gene product. CDX-2 activity also increases along the crypt-villus axis, lowest in the proliferative cell fraction in the crypt and highest in differentiated enterocytes at the lumenal surface. Expression of GC-C is highly conserved, whereas that of the endogenous ligands of this receptor, guanylin and urogunalyin, is significantly reduced, in colorectal cancer tumors, suggesting decreased GC-C activity may contribute to colon tumorigenesis. Moreover, the GC-C ligands ST and uroguanylin inhibit the proliferation of colorectal cancer cells, mediated by cGMP-dependent activation of CNG channel and Ca²⁺ influx. These observations suggest a critical role for GC-C and its downstream signaling mechanism in the (patho) physiology of the intestine.