The mechanisms controlling the sphincter of Oddi (SO) have received considerable attention over the past two decades. Progress towards their elucidation has been slow, perhaps because of the sphincter's relative inaccessibility and the different responses of the human "resistor" as compared to the "pumper" observed in several animal models. The list of agents affecting the sphincter grows alarmingly. In this review, divided into two parts, substances have been classified as neurotransmitters, hormones, local factors and pharmacological agents. The first part considers the roles of neurotransmitters. These include (a) vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). Both cause relaxation. A recent model of their complex interrelationships in smooth muscle is described. (b) Substance P (SP) and enkephalins. These produce contractions. The former can act directly. An indirect effect via cholinergic neurones may be the result of SP release from vagal afferents. (c) Catecholamines, which cause contraction or relaxation via activation of alpha- or beta-adrenoreceptors, respectively. In the second part attention is focussed on cholecystokinin (CCK) which normally relaxes the SO via neuronal mechanisms. A CCK-sensitive pathway from sensory duodenal neurones to SO ganglia has been described. Reactive oxygen species are among the local factors discussed. Their description as being "the good, the bad and the ugly" seems merited. Pharmacological agents include NO donors, octreotide and botulinum toxin (BTX). Octreotide induces tachyoddia and may impair biliary flow. BTX has exciting potential in the diagnosis of SO abnormalities and as a therapeutic alternative to sphincterotomy. In both parts of the review current concepts of different aspects of smooth muscle control are presented. In several instances data regarding the SO is lacking. We discuss (a) the role of interstitial cell of Cajal in the control of slow waves, (b) different pathways contributing to tonic and phasic contractions, (c) the 4 levels of neural control, (d) interrelationships of immune and nervous systems, and (e) links between emotional states and gut functions.