Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain associated with defecation with altered stool frequency or stool form. The global prevalence of IBS ranges from 10% to 15% and total healthcare cost attributable to IBS is significant. Among individuals with IBS, the condition has dramatic effects on health-related quality of life, work and school productivity, and activities of daily living. It may be diagnosed with confidence, based on symptom-based diagnostic criteria, exclusion of alarm features and directed diagnostic testing. Management of IBS typically begins with dietary and lifestyle modifications, progressing to over-the-counter therapies, and then to prescription medications, both approved and nonapproved for IBS. This narrative summarizes the efficacy and safety of three US Food and Drug Administration (FDA)-approved prescription therapies for IBS with diarrhea (IBS-D), with a focus on the most recently marketed agent, eluxadoline, and its role in the treatment IBS-D.