Serotonin type-3 receptor (5-HT₃) antagonists revolutionized the chemotherapy field being safe and effective agents for the acute treatment of chemotherapy-induced nausea and vomiting (CINV). Functionally, the 5-HT₃ receptor is a ligand-gated ion channel which mediates fast synaptic neurotransmission in the CNS and periphery. Its structural uniqueness within the serotonin receptor family has made the 5-HT₃ receptor an attractive target for disease intervention. Recently, firm clinical support has emerged for the treatment of irritable bowel syndrome (IBS) and schizophrenia with 5-HT₃ modulators. The opportunity to add treatment options for chronic diseases like IBS prompted us to search for a new class of 5-HT₃ receptor antagonists. 2-Arylbenzoxazole carboxamides were discovered as potent, orally active 5-HT₃ receptor antagonists with good metabolic stability. Early structure-activity relationships and efficacy assessment will be described.