Recent discoveries regarding the relatively autonomous workings of the enteric nervous system have expanded our understanding of the pathophysiology of irritable bowel syndrome (IBS). However, the heterogeneity of the pathogenesis of IBS continues to create unique challenges for clinicians who care for these patients. Advances in our understanding of the structure and functions of the brain-gut axis and its interplay with other potentially important factors, such as genetic predisposition, inflammation, and psychological unrest, have led to new developments in the field of targeted pharmacotherapy for IBS sufferers. Therapies designed specifically to modulate gut motility, secretion, and/or sensation have been created and introduced into the marketplace in recent years, and additional designer formulations are in various stages of development. Concurrently, new discoveries of potentially beneficial effects of agents approved for other, often non-gastroenterologic, conditions continue to be reported. This article reviews the accumulating body of evidence supporting the importance of neuromuscular dysfunction as a central cause of IBS symptoms and provides a rationale for the discussion of current and future drug development.