Purpose of Review: Production of cyclic guanosine monophosphate (cGMP) by guanylate cyclase is of critical importance to gastrointestinal physiology. Tight regulation of cGMP concentration is necessary for proper intestinal secretion and intestinal epithelial cell proliferative and apoptotic homeostasis. This review focuses on recent work detailing the role of a subset of transmembrane guanylate cyclases in the pathophysiology of intestinal secretory and motility disorders and intestinal epithelial cell transformation. Also considered is the potential for therapeutic manipulation of intestinal guanylate cyclase/cGMP signaling for the correction of chronic constipation and gastrointestinal cancer. Recent Findings: Recent work in mice and humans suggests a role for transmembrane guanylate cyclases in intestinal fluid secretion as well as hormonal enteric-renal signaling which mediates postprandial natriuresis. Transmembrane guanylate cyclases are also important in gastrointestinal transit rate and motility. Ongoing clinical trials have found that guanylate cyclase activating peptides are safe and effective in the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. In addition, accumulating evidence indicates that membrane-associated guanylate cyclase receptors regulate intestinal epithelial cell homeostatic proliferation and apoptosis as well as gastrointestinal malignancy. The anticancer activity of cGMP signaling in animal studies suggests additional therapeutic applications for guanylate cyclase agonists. Summary: Progress toward understanding gastrointestinal transmembrane guanylate cyclase/cGMP physiology has recently accelerated due to definitive in-vitro studies and work using gene-targeted animal models and has facilitated the development of safe and effective drugs designed to regulate cGMP production in the intestine. Current work should be directed toward a detailed understanding of cGMP effector pathways and the manner in which subcellular concentrations of cGMP regulate them to influence intestinal health and disease. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.