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Increased resistance to portal blood flow leading to portal hypertension is the main cause of morbidity and mortality in patients with chronic liver disease, and reflects two parallel yet interrelated processes. First, the wound healing response to liver injury generates increased extracellular matrix (fibrosis) and the formation of regenerative nodules, which lead to architectural distortion that impedes intrahepatic blood flow. Second, dynamic sinusoidal changes caused by increased contractility of stellate cells in the perisinusoidal space also increase intrahepatic vascular resistance. The relative contribution of each of these components is difficult to quantify and may vary with the etiology and stage of fibrosis, but together they represent a key target for antifibrotic and vasoregulatory therapies. Clearly, the most effective therapy to treat hepatic fibrosis is to remove the causative agent. However, therapies that are able to retard or reverse the fibrotic response and/or inhibit stellate cell contraction could have a dramatic impact on the treatment of patients with chronic liver disease. This chapter reviews the cellular basis of hepatic fibrosis and increased intrahepatic vascular resistance, and how these insights are yielding novel approaches to the treatment of chronic liver disease. [ABSTRACT FROM AUTHOR]