There is a clear unmet need for new treatments in irritable bowel syndrome with diarrhea (IBS-D). Ondansetron, an old 5-hydroxy-tryptamine3 antagonist, used for chemotherapy-induced nausea and vomiting and with favorable side effect profile, has shown promising results in previous trials. In this issue, efficacy with a novel bimodal release ondansetron formulation was presented in IBS-D. The bimodal release ondansetron improved stool consistency, presumably by slowing transit time, and tended to improve other IBS symptoms as well. The authors proposed C-reactive protein levels as a tool to select responders because a better response was seen in patients with slightly elevated C-reactive protein levels. Future large-scale studies will determine the role of bimodal release ondansetron in IBS-D with and without low-grade inflammation.