Portal hypertension is the final common pathway in patients with chronic liver disease, and often the driver of clinical signs and symptoms of cirrhosis or acute severe liver injury. The development of these represents decompensation and is an independent marker of a dramatically worsened prognosis. The mechanisms that underlie portal hypertension are complex, involving hepatic fibrosis as well as multiple chemical mediators that drive vasoconstriction and vasodilatation—some of which can be impacted by medical therapies, as well as treatment of the underlying disease process. Hepatic venous pressure gradient measurement is the gold standard for prognostication and has become a surrogate target for medical therapies. Effective reduction of portal pressure has long been known to have a high likelihood of preventing variceal bleeding or rebleeding, but recent data suggest that it may also prevent the risk of progression of liver disease and its complications. In response, increasingly sophisticated diagnostic algorithms have been proposed, combining lab testing and liver stiffness measurements, which are able to discriminate among patients with different causes of liver disease with high sensitivity and specificity for the detection of clinically significant portal hypertension.