Guanylyl cyclase C (GUCY2C) is a membrane-bound receptor that produces the second messenger cGMP following activation by its hormone ligands guanylin or uroguanylin, regulating intestinal homeostasis, tumorigenesis, and obesity. In turn, cGMP signaling regulates homeostatic processes in intestine that are canonically disrupted in cancer, including maintenance of DNA integrity and genomic stability. GUCY2C is expressed mostly on the apical surface of intestinal cells but also in the kidney, airway epithelium, perinatal liver, stomach, brain, adrenal glands, and reproductive tissues. Analogous to other rGCs, the primary sequence of GUCY2C reveals a multidomain architecture. Residues 1-23 comprise a putative signal peptide that directs the receptor to the cell surface. This is followed by the ECD (residues 24-430). The intracellular region has a short juxta-membrane domain (residues 455-489) which is followed by a kinase-homology domain (KHD) (residues 490-735), the linker region (residues 736-810), the guanylyl cyclase domain (GCD) (residues 811-1,010), and a C-terminal domain (CTD) (residues 1,011-1,073). Guanylyl cyclase C receptor (GUCY2C) and its hormones, uroguanylin and guanylin, have emerged as a key signaling axis opposing mutations driving intestinal tumorigenesis.