5-HT4 receptors are G protein-coupled receptors that link to the stimulatory protein Gs which activates adenylate cyclase to increase intracellular cyclic AMP which then activates protein kinase A (PKA). 5-HT4 receptors are expressed by neurons in the central and peripheral nervous systems especially the enteric nervous system (ENS). In general, 5-HT4 receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5-HT4 receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of Neurogastroenterology and Motility features two novel 5-HT4 receptor agonists (5-HT4 -LA1 and 5-HT4 -LA-2) that are not absorbed from the gastrointestinal tract of mice and act locally in the colonic mucosa to stimulate propulsive motility. The authors show that 5-HT4 -LA1 and 5-HT4 -LA2 were not absorbed from the colon and that both drugs stimulated colonic transit when administered by gavage. Both agonists stimulated colonic glass bead expulsion, and 5-HT4 LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5-HT4 receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5-HT4 receptor agonists that have prokinetic actions on the GI tract. These drugs are not absorbed and act locally in the gut mucosa to stimulate propulsive motility while minimizing access to systemic 5-HT4 receptors and avoiding potential unwanted side effects.