Serotonin (5-HT) is a crucial signaling molecule in the gastrointestinal (GI) tract, with roles in motility, secretion, vasodilation, and pain perception. It is synthesized and stored in enterochromaffin (EC) cells in the intestinal mucosa, where it is released and acts on various 5-HT receptors on intrinsic and extrinsic afferent nerve fibers. 5-HT also plays a role in non-conventional functions, such as promoting neuronal development and acting as a pro-inflammatory mediator. Platelet-derived 5-HT can influence hemostasis, bone development, and allergic airway inflammation. 5-HT receptor antagonists and agonists are used to treat functional GI disorders, such as diarrhea and constipation. Recent studies have identified new therapeutic targets, including tryptophan hydroxylase and epithelial 5-HT4 receptors, which may offer safer and more effective treatments for constipation. In pathophysiological conditions, such as inflammatory bowel disease (IBD) and functional GI disorders, 5-HT signaling is altered, with changes in 5-HT content, EC cell numbers, and SERT expression. These changes can affect GI function and sensation. In IBS, reduced SERT expression is associated with altered 5-HT availability, leading to symptoms like diarrhea and constipation. The role of 5-HT in GI motility, secretion, and pain perception is well-established, with 5-HT3 and 5-HT4 receptors being key targets for therapeutic intervention. 5-HT3 antagonists are used to treat nausea and vomiting, while 5-HT4 agonists are used to treat constipation. However, some 5-HT4 agonists have been withdrawn due to cardiovascular side effects, prompting the development of more selective agents. 5-HT also plays a role in non-GI functions, such as bone density regulation and allergic airway inflammation. TpH1 inhibitors have been tested as potential therapies for these conditions. The gut is a major source of 5-HT, which can influence various tissues outside the GI tract. Understanding the complex roles of 5-HT in the GI tract and its interactions with other systems is essential for developing effective treatments for GI disorders.Serotonin (5-HT) is a crucial signaling molecule in the gastrointestinal (GI) tract, with roles in motility, secretion, vasodilation, and pain perception. It is synthesized and stored in enterochromaffin (EC) cells in the intestinal mucosa, where it is released and acts on various 5-HT receptors on intrinsic and extrinsic afferent nerve fibers. 5-HT also plays a role in non-conventional functions, such as promoting neuronal development and acting as a pro-inflammatory mediator. Platelet-derived 5-HT can influence hemostasis, bone development, and allergic airway inflammation. 5-HT receptor antagonists and agonists are used to treat functional GI disorders, such as diarrhea and constipation. Recent studies have identified new therapeutic targets, including tryptophan hydroxylase and epithelial 5-HT4 receptors, which may offer safer and more effective treatments for constipation. In pathophysiological conditions, such as inflammatory bowel disease (IBD) and functional GI disorders, 5-HT signaling is altered, with changes in 5-HT content, EC cell numbers, and SERT expression. These changes can affect GI function and sensation. In IBS, reduced SERT expression is associated with altered 5-HT availability, leading to symptoms like diarrhea and constipation. The role of 5-HT in GI motility, secretion, and pain perception is well-established, with 5-HT3 and 5-HT4 receptors being key targets for therapeutic intervention. 5-HT3 antagonists are used to treat nausea and vomiting, while 5-HT4 agonists are used to treat constipation. However, some 5-HT4 agonists have been withdrawn due to cardiovascular side effects, prompting the development of more selective agents. 5-HT also plays a role in non-GI functions, such as bone density regulation and allergic airway inflammation. TpH1 inhibitors have been tested as potential therapies for these conditions. The gut is a major source of 5-HT, which can influence various tissues outside the GI tract. Understanding the complex roles of 5-HT in the GI tract and its interactions with other systems is essential for developing effective treatments for GI disorders.