In addition to the classical transmitters noradrenaline and acetylcholine, other transmitters have been identified in perivascular nerves, including 5-hydroxytryptamine, ATP and a number of peptides. This paper discusses pre- and postjunctional neuromodulation of vascular transmission, and cotransmission involving noradrenaline, ATP and neuropeptide Y in sympathetic nerves, acetylcholine and vasoactive intestinal polypeptide in parasympathetic nerves, and substance P, calcitonin gene-related peptide and ATP in 'sensory-motor' nerves. Vasomotor nerves derived from intrinsic neurones, for example in the heart and gut, are also discussed. Subpopulations of endothelial cells store and release a variety of substances, including acetylcholine, substance P, ATP, 5-hydroxytryptamine, vasopressin and angiotensin II, that act on receptors on endothelial cells and lead to the production of endothelium-derived relaxing factor (identified as nitric oxide) which, in turn, produces vasodilation in response to changes in flow and hypoxia. Endothelium-derived contracting factors such as endothelin may also be released. There appears to be a resting dynamic balance between endothelium-derived vasodilator tone and sympathetic vasoconstrictor tone, which is altered under different physiological and pathophysiological circumstances. Long-term (trophic) interactions between perivascular nerves and endothelial cells are discussed, as are the changes in vascular control mechanisms that occur with ageing and hypertension and in the nerves that remain following trauma or surgery.