In the last decade, the knowledge of the pathogenesis of portal hypertension and cirrhosis has increased dramatically. In portal hypertension, almost all the known vasoactive systems/substances are activated or increased and the most recent studies have stressed the importance of the endothelial factors, in particular, prostaglandins. Prostaglandins are formed following the oxygenation of arachidonic acid by the cyclooxygenase (Cox) pathway. An important consideration in portal hypertension and cirrhosis in the periphery is the altered hemodynamic profile and its contributory role in controlling endothelial release of these vasoactive substances. Prostaglandins are released from the endothelium in response to both humoral and mechanical stimuli and can profoundly affect both intrahepatic and peripheral vascular resistance. Within the liver, intrahepatic resistance is altered due to a diminution in sinusoidal responsiveness to vasodilators and an increase in prostanoid vasoconstrictor responsiveness. This review will examine the contributory role of both hormonal and/or hemodynamic force-induced changes in prostaglandin production and signaling in cirrhosis and portal hypertension and the consequence of these changes on the structural and functional response of both the vasculature and the liver.