In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.