Background: Portal hypertension is the haemodynamic abnormality associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy and bleeding from gastro-oesophageal varices. Pharmacological and endoscopic treatment of portal hypertension has played an increasing clinical role in the past 30 years. Despite the progress achieved over the last decades, the 6-week mortality associated with variceal bleeding is still in the order of 10–20%. In the setting of acute variceal bleeding, drug and endoscopic therapy should be considered the initial treatment of choice and can be administered as soon as possible. Management of treatment of portal hypertension and variceal hemorrhage is based on the clinical stage of portal hypertension. Prevention of first variceal hemorrhage depends on the size of varices. In patients with small varices and high risk of bleeding, non-selective β-blockers are recommended, while patients with medium/large varices can be treated with either β-blockers or oesophageal band ligation. Standard of care for acute variceal hemorrhage consists of vasoactive drugs, endoscopic band ligation and antibiotics prophylaxis. Patients who had failed this therapy should be considered for transjugular intrahepatic portosystemic shunt or shunt surgery. Prevention of recurrent variceal hemorrhage consists of the combination of β-blockers ± isosorbide 5-mononitrate and endoscopic band ligation. Patients with recurrent variceal hemorrhage are in a category of “further decompensation” of cirrhosis and, as such, should be evaluated for liver transplantation. Conclusions: In the last decades significant advances in the field of portal hypertension have improved the clinical care and survival of patients with cirrhosis and portal hypertension. Further research is necessary to explore new pharmacological options that would allow to get a positive hemodynamic response in most patients.