Current understanding of the pathophysiology of portal hypertension has resulted in therapeutic approaches aimed at correcting the increased splanchnic blood flow and some of which have been already used in clinical practice. Recently new perspectives opened and erstwhile paradigm has been changed to focus on increased resistance to portal blood flow and the formation of portosystemic collateralization. Several studies revealed the clear-cut mechanisms of hepatic endothelial dysfunction and abnormal angiogenesis contributing to the development of portal hypertension. Thus the modulations of hyperdynamic circulation or angiogenesis seem to be valuable therapeutic targets. In the current review update, we discuss the multidisciplinary management of modulating hepatic vascular resistance and abnormal angiogenesis associated with portal hypertension. However, these new pharmacological approaches are still under investigation and widescale clinical application are needed to develop effective strategies.