There is still no agreement over optimal pharmacological treatment for irritable bowel syndrome (IBS). Patients with IBS and diarrhea (IBS-D) demonstrate both visceral hypersensitivity and impaired colonic motility with increased frequency and amplitude of giant migrating contractions (GMCs) which cause mass movements, propulsion of stools and initiation of defecation. Both antispasmodics and 5-HT3 receptor antagonists can improve the symptoms and the impaired colonic motility of patients with IBS-D though through very different mechanisms. Antispasmodics act by directly relaxing the colonic smooth muscle cells or antagonizing the excitatory neuromuscular neurotransmission. In contrast, the mechanism of action of 5HT3 antagonists is much more complex and subtle as they inhibit the ascending excitatory component of the peristaltic reflex and GMCs. There are some concerns about the safety of 5HT3 antagonists in long-term treatment. Most of the studies on the treatment of IBS have followed the pharmacological strategy of looking for big clinical effects acting on a single receptor/target. We propose a pharmacologic strategy which uses different drugs for pain and dysmotility in the same patient and includes specific drugs acting on smooth muscle cells, neuromuscular transmission, synaptic transmission and intrinsic afferents. The clinical effect on IBS symptoms would be found in the sum of all these smaller effects on multiple targets.