Interstitial cells of Cajal (ICC) control gastrointestinal motility; some pace slow waves and others act in enteric neurotransmission. This review asks the question, does either class of ICC receive and respond to messages carried by neuromediators from these nerves? Relevant evidence includes the presence of receptors or responses to exogenous neuromediators and responses to endogenous neuromediators. Some pacemaking ICC networks have receptors for or respond to some exogenous neuromediators. None is known to respond to endogenous neuromediators. Intramuscular ICC have receptors for and respond to some neuromediators and are required in mice for responses to the exogenous and endogenous neuromediators nitric oxide and acetylcholine. The mechanisms underlying this requirement remain unclear. ICC pathologies exist, but their origins are unknown.