Irritable Bowel Syndrome (IBS) is a significant problem that affects a large proportion of the US population. The past several years have seen advances in our understanding of the pathophysiology associated with IBS and the development of new therapies. Older therapies have few well-designed clinical studies to support their use. The older studies tended to evaluate the impact of therapy on only one symptom and were ineffective at improving the overall symptomology in this functional disorder. In addition, the older drugs tended to produce side effects that often led to discontinuation of the therapy. Newer therapies, such as the FDA approved serotonergic agents (eg, alosetron and tegaserod), target abnormalities in gut physiology seen in IBS and not just the symptomatic presentation of the disease. In women, these medications have shown to be effective treatments for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Pending FDA approval, cilansetron represents the second 5-HT3 antagonist for the treatment of IBS-D. It has shown promising results in both men and women, which is an improvement over alosetron, since it is only approved for use in females. Similar to alosetron, the most common side effect seen with cilansetron therapy is constipation. Few cases of ischemic colitis, like those seen during alosetron therapy, have been reported in the cilansetron clinical trials and all have resolved without complication. A thorough review of the available data regarding cilansetron will be discussed in this article.