Preclinical experiments in rodent models have recently provided new information on the mechanisms underlying pain sensation in chronic visceral hypersensitivity, as well as insights into the mechanism of action of new drugs targeting abdominal pain in irritable bowel syndrome (IBS). This article describes the evidence base supporting the role of guanylate cyclase C (GC-C) activation in the modulation of gastrointestinal transit and, in particular, in visceral hypersensitivity. We propose that GC-C activation represents an important emerging target for pharmacotherapy in IBS with constipation (IBS-C), particularly given the recent regulatory approval of the GC-C agonist linaclotide as a treatment for IBS-C. More specifically, we address the following questions: "How is pain transmitted from the colon?"; "How is abdominal pain increased in IBS-C?"; "How can we reduce IBS-related abdominal pain - what drugs have been developed?"; "Does linaclotide reduce abdominal pain in animals and humans?"; and "How does linaclotide reduce abdominal pain?".