Torunn Fiskerstrand and colleagues report an activating mutation in GUCY2C as the cause of an autosomal dominant diarrhea syndrome in a large Norwegian family (N. Engl. J. Med., published online 21 March 2012; doi: 10.1056/NEJMoa1110132). The authors mapped the disease locus to a 2.9-Mb region on chromosome 12 by using linkage analysis. They then sequenced the most promising candidate gene in the region, GUCY2C, which encodes a transmembrane guanylate cyclase that functions as an intestinal receptor for bacterial endotoxins, and identified a missense variant (encoding p.Ser840Ile) that co-segregated with the disease in the family. The altered residue is located in the protein's catalytic domain and leads to higher guanylate cyclase activity following ligand stimulation, resulting in increased cyclic GMP production. The authors propose that the elevated cyclic GMP levels stimulate activity of the CFTR chloride channel, resulting in increased water efflux into the intestinal lumen. The authors note that the disease symptoms in this family overlap with those seen in other diseases, including Crohn's disease and irritable bowel syndrome, suggesting that deregulation of this guanylate cyclase pathway could contribute to more common forms of inflammatory bowel disease.