We have come a long way from the original concept of portal hypertension as a simple reflection of obstruction or fixed resistance to portal flow within the diseased liver. In an individual patient or a given clinical situation, the induction and maintenance of portal hypertension depends on the interaction between several factors that include (Table 2; Fig. 1): 1) fixed resistance within a cirrhotic or fibrosus liver or an obstructed venous system; 2) the balance at the sinusoidal level between vasoconstriction and vasodilation, perhaps mediated by the effects of endothelin or nitric oxide, respectively, on stellate cells; 3) splanchnic hyperemia, dependent, in turn, on the interplay, in the splanchnic vascular bed, between vasodilatory (nitric oxide and prostacyclin, in particular) and vasoconstrictor substances; 4) collateralization; and 5) changes in plasma volume. Plasma volume increases from sodium retention (4), also mediated, at least in part, by atrial natriuretic factor (39). The recent experience with β-blockers in the therapy of portal hypertension points to the importance of recognizing each of these factors and their relative contribution in a given circumstance. Based on currently available information, one could propose a variable contribution of these factors, depending on the stage of the underlying liver diseases, as follows. In the patient with portal hypertension but without liver disease or varices, sinusoidal vasoconstriction may be the primary pathogenetic factor. When cirrhosis supervenes and especially when it is complicated by ascites and collateralization, splanchnic hyperemia, mediated by endotoxin-induced expression of iNOS and sustained by flow-induced induction of cNOS and the development of vasoconstrictor hyporeactivity within the splanchnic vascular bed, becomes more important. As liver disease progresses, associated hyperdynamic circulatory changes mediated by similar factors develop. At this stage, variations in resistance within collaterals, which are now extensive, comes to exert an important regulatory role.