The evidence for an impact of platelet-derived 5-hydroxytryptamine (5-HT) on local tissue perfusion is reviewed. By interacting with 5-HT2 serotonergic receptors, 5-HT, directly or through amplification, activates platelets, endothelial and vascular smooth muscle cells producing platelet aggregation, vascular permeability increase and large vessel constriction. Pharmacodissection in experimental animals with selective serotonergic 5-HT2 receptor antagonists, e.g. ketanserin, shows that 5-HT largely contributes to the platelet-mediated increase in vascular permeability, to platelet-vessel wall interaction during hemostasis, to cardiopulmonary dysfunction provoked by thromboembolism and to the platelet-mediated inhibition of peripheral collateral circulation. Clinical results obtained with ketanserin further substantiate an involvement of platelet-derived 5-HT in the pathogenesis of impaired tissue perfusion in some cardiovascular conditions.