In vitro investigations have identified three major mechanisms which could contribute to the vasodilator action of serotonin (5-hydroxytryptamine, 5-HT): direct vascular smooth muscle relaxation; prejunctional inhibition of noradrenaline release from vascular sympathetic nerve terminals; and release of endothelium-derived relaxing factor (EDRF). In vivo studies have shown that in pig and cat common carotid circulations, rabbit hind-quarter and mesenteric circulations, and rat systemic vasculature, direct vascular smooth muscle relaxation may be the predominant mechanism involved, but the contribution of EDRF release remains to be established. In other circulations in vivo (dog femoral and common carotid), prejunctional inhibition of vascular sympathetic tone is the predominant mechanism responsible for serotonin-induced vasodilatation. All of these actions are mediated by 5-HT<sub>1</sub>-like receptors, but different subtypes seem to be involved in each of these mechanisms. The prejunctional inhibitory receptor has been the most studied; depending on the tissue, these subtypes may resemble 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1c</sub> or 5-HT<sub>1D</sub> binding sites, or the contractile receptor in dog saphenous vein.