It is now well established that portal hypertension is not a purely mechanical phenomenon. Primary hemodynamic alterations develop in the hepatic and systemic circulatory systems; these alterations in combination with mechanical factors contribute to the development of portal hypertension. In the hepatic circulation, these hemodynamic alterations are characterized by vasoconstriction and impaired hepatic vasodilatory responses, whereas in the systemic circulation, particularly in the splanchnic bed, vessels are hyperemic with increased flow. Thus, an increase in intrahepatic resistance in conjunction with increased portal venous inflow, mediated through splanchnic dilation, contributes to the development of portal hypertension. The ensuing development of elevated flow and transmural pressure through collateral vessels from the hypertensive portal vasculature into the lower pressure systemic venous circulation accounts for many of the complications, such as bleeding esophageal varices, observed with portal hypertension. The importance of the primary vascular origin of portal hypertension is emphasized by the utility of current therapies aimed at reversing these hemodynamic alterations, such as nitrates, which reduce portal pressure through direct intrahepatic vasodilatation, and ,B blockers and octreotide, which reduce splanchnic vasodilatation and portal venous inflow. New evidence concerning relevant molecular mechanisms of contractile signaling pathways in hepatic stellate cells and the complex regulatory pathways of vasoactive molecules in liver endothelial cells makes a better understanding of these processes essential for developing further experimental therapies for portal hypertension. This article examines the current concepts relating to cellular mechanism that underlie the hemodynamic alterations that characterize and account for the development of portal hypertension.