ATP is an important neurotransmitter being released with noradrenaline (NA) and neuropeptide Y (NPY) from perivascular sympathetic nerves; it acts at postjunctional P2X receptors to evoke vascular smooth muscle contraction, often synergising with the effects of NA acting at α-adrenoceptors. There is growing evidence for ATP as a neurotransmitter in perivascular non-adrenergic non-cholinergic nerves. In addition, ATP can act as a facilitatory and inhibitory neuromodulator via prejunctional P2 receptors. ATP is rapidly broken down, by ectonucleotidases, to adenosine which can also regulate the release of neurotransmitters via inhibitory prejunctional A1 adenosine receptors. The relative contributions of ATP and NA as functional cotransmitters varies with species, age, type and size of blood vessel, frequency and duration of stimulation, the tone/pressure of the blood vessel, and in disease. Blood vessel tone/pressure itself can be influenced by the vasocontractile and vasorelaxant actions of purines at different subtypes of P1 and P2 receptors, following release from the endothelium, smooth muscle, erythrocytes and platelets, as well as from perivascular nerves. This review focuses on the role of ATP as a cotransmitter in perivascular nerves in physiological and pathophysiological conditions; neuromodulator roles of purines are also discussed.