The regulation of smooth muscle relaxation is vitally important for normal functioning of respiratory airways, gastrointestinal organs and the circulatory system. Since the recognition that such relaxation is not under adrenergic or cholinergic control, there has been an active search for the nonadrenergic, noncholinergic (NANC) mediators. A recent paper highlights the complex but coordinated control of the internal anal sphincter by three neurotransmitters.