Control of motor patterns in visceral organs comes from multiple layers of regulatory mechanisms that start with the properties of smooth muscle cells that permit contractile behaviour or precondition cells for contraction or relaxation when other stimuli are overlaid. Like other motor systems in the body, visceral organs including the gastrointestinal (GI) tract are controlled by a variety of neural and non-neural factors. For example, spontaneous electrical activity, intrinsic to many smooth muscle tissues, is generated by a specialized population of cells called interstitial cells of Cajal (ICC) that are electrically coupled to the smooth muscle cells. In addition to this level of control, inputs from the enteric nervous system (ENS), hormonal influences, and paracrine factors regulate motor activity during normal physiological responses. Inflammatory mediators contribute additionally during the course of pathophysiological conditions. Smooth muscle cells integrate the inputs from all levels of control and respond in normal individuals with appropriate contractile responses. In the GI tract ICC, usually located along the intermuscular plane between the circular and longitudinal muscle layers, generates pacemaker potentials that are conducted passively into the adjacent muscle layers via gap junctions where they produce rhythmical membrane potential changes that regulate phasic contractions (1). The mechanical activity of GI smooth muscle cells, can be altered by autonomic, or enteric, nerves innervating them. Previously it was thought that neuroeffector transmission occurred simply because neurally released transmitters acted directly on smooth muscle cells. However, in several, regions of the GI tract, it appears that nerve terminals, rather than communicating directly with smooth muscle cells, preferentially form synapses with ICC and these relay information to neighbouring smooth muscle cells (2). Thus a set of ICC, which are distributed amongst the smooth muscle cells of the gut, are the targets of neurotransmitters released by intrinsic enteric excitatory and inhibitory nerve terminals. In some regions of the GI tract, the same set of ICC also augment the waves of depolarisation generated by pacemaker ICC. Similarly in the urethra, ICC, distributed amongst the smooth muscle cells, generate rhythmic activity and also appear to be the targets of autonomic nerve terminals (3). A second interstitial cell, recently identified based on the expression of platelet-derived growth factor receptor-α (PDGFRα), which previously referred to as “fibroblast-like” were observed in close association with enteric nerve fibers (4) PDGFRα+ cells express SK3 potassium channels which are sensitive to the bee venom apamin. Activation of inhibitory motor nerves produces a post-junctional response that is mediated through purines acting on P2Y1R receptors and is inhibited by apamin. Further, isolated PDGFRα+ cells, unlike smooth muscle cells, produce robust outward currents in response to purines which were blocked by apamin and selective P2Y1R antagonists (5). It is therefore likely that PDGFRα+ cells generate inhibitory post-junctional responses and like ICC contribute to neuroeffector motor neurotransmission in GI muscles. There is also a significant body of functional immunohistochemical evidence that reveals ICC and now a second population of interstitial cells that are PDGFRα+, are transducers and integrators of motor neurotransmitter signals. Thus, neuromuscular regulation of GI muscles is likely to include multiple modes of neurotransmission (volume and synaptic) and several cell types may receive and transduce inputs from motoneurons. In summary, motor activity and inputs from excitatory/inhibitory motor nerves in visceral smooth muscles is fundamental to normal organ function. An understanding how this motor activity is properly coordinated by inputs from pacemaker ICC and by intramuscular interstitial cells (ICC and PDGFRα+ cells) that act as intermediaries in motor transmission is critical for a complete understanding of how visceral organs perform their functions in health, before we attempt to unravel the changes that occur in the pathophysiological states of disease.