&NA;The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of liberation of endothelium‐derived relaxing factor (EDRF) from endothelial cells. Some blood vessels contain a substantial population of medial constrictor receptors for acetylcholine, and the implications of this presence for vascular control systems has been largely ignored, although it needs to be considered. A survey of the evolution of vasomotor control systems indicates that acetylcholine serves principally as an excitatory transmitter to blood vessels. Neurally mediated cholinergic constriction and not dilation is found in fish, amphibians, reptiles, and birds, with responses initiated by medial muscarinic receptors. Acetylcholine constricts many vascular preparations from these lower animals, but some vessels relax, reflecting the emergence of an EDRF responsive to acetylcholine. An examination of cholinergic responses in mammalian vessels reveals that cholinergic (neurogenic) dilation is limited to a very few vascular beds and to only a few species. Both experimental evidence and evolutionary considerations support the likelihood that cholinergic (neural) constriction operates in some vascular regions in mammals and, in particular, in the coronary circulation of some species, including humans. In fact, constriction, and not dilation, may be the dominant vascular response to activation of the cholinergic axis in most mammals, including humans. The complications and contradictions introduced by the simultaneous presence of both EDRF and a cholinergic constrictor innervation involving medial muscarinic receptors are discussed. A variety of evidence is also presented that implicates cholinergic constriction in at least some instances of coronary artery spasm and sudden death. (Circulation Research1989;65:237‐257)