For over 30 years, nonselective beta-blockers (NSBB) have been successfully used for preventing variceal bleeding in patients with cirrhosis and portal hypertension. Nevertheless, recent studies suggest that NSBB may be effective only within a particular "therapeutic window" in patients with advanced liver disease. Outside of this window, in early stages of cirrhosis and in very advanced cirrhosis, NSBB may be ineffective and even potentially harmful. In this paper we review the beneficial effects and potential harms of beta-blocker therapy in cirrhosis and underline the most recent recommendations for their use in very advanced cases of liver disease.