Since the discovery of the impact of serotonin in liver regeneration, this molecule has gained considerable attention in liver physio-pathology. Platelet-derived serotonin initiates liver regeneration after partial hepatectomy in various rodent models. Serotonin agonism stabilizes the hepatic microcirculation and prevents small-for-size liver graft failure. Similarly, serotonin receptor agonists improve the sinusoidal perfusion of aged liver and restore the deficient liver regeneration in old mice through a pathway dependent on vascular endothelial growth factor. Beside hepatocyte proliferation, cholangiocytes have been shown to be able to deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree. Increasing evidence indicates that serotonin is involved in many pathological conditions of the liver. For example, serotonin promotes tissue repair after ischemia/reperfusion injury. Reactive oxygen species generated by serotonin degradation contribute to steatohepatitis in rodent models. Serotonin aggravates viral hepatitis, again through vasoactive effects on the microcirculation, and plays a crucial role in the progression of hepatic fibrosis. Finally, serotonin may facilitate tumor growth of primary liver carcinoma like cholangiocarcinoma and hepatocellular carcinoma. These findings make serotonin both friend and foe for the liver. Whichever, these new data emphasize the potential of serotonin as a pharmacological target in liver disease.