Liver regeneration is triggered by acute loss of a large number of hepatocytes after surgical resection (modeled by two-thirds partial hepatectomy [PH] in rats and mice) or acute chemical injury (modeled by injection of CCl4 or acetaminophen). Most of the studies in the last three decades have focused on signaling mechanisms at the beginning of regeneration, associated with triggering of hepatocyte proliferation. 1-3 The preponderance of evidence has shown that proliferating hepatocytes generate signals that trigger proliferation of hepatic nonepithelial cells. Regeneration is a “give and take” arrangement in which hepatocytes provide mitogenic signals for endothelial cells and macrophages (secrete vascular endothelial growth factor and granulocyte-macrophage colony-stimulating factor, respectively) and receive hepatocyte growth factor (HGF), interleukin-6, and tumor necrosis factor alpha in return. Stellate cells produce HGF; fibroblast growth factor 1/2, generated by replicating hepatocytes, is mitogenic for stellate cells. Hepatocytes are the main functional cells of the liver, and the objective of regeneration is to result in a happy ending in which the number of hepatocytes returns to a value sufficient to assure normal hepatic contributions to body homeostasis. In view of the above, it is not surprising that hepatocytes would also play an important role at the other end of regeneration: the termination stage. Liver regeneration studies, from the earliest by Higgins and Anderson in rats to later studies in mice, have shown that most hepatocyte proliferation is over by days 6-8, whereas liver mass is mostly restored by day 15. 4 Study of the signaling involved in initiation of liver regeneration is easier because initiation of regeneration is associated with an acute event (hepatectomy, chemical injury, and so on). The termination phase is not associated with a precisely timed event, and this makes it difficult to pinpoint the associated signals. Adding to the complication is evidence from studies showing that more hepatocytes than needed may be generated by the end of regeneration, and a small wave of apoptosis may be needed to correct the imbalance. 5 Several extracellular signals to hepatocytes have been considered as playing a role in the termination stage. Transforming growth factor beta 1 (TGF-b1), an inhibitor of hepatocyte proliferation, has been often implicated in termination signaling. Immunoreactive TGF-b1 is gradually removed from periportal toward centrilobular hepatocytes during regeneration. 6 However, overexpression of TGF-b1 does not significantly affect liver regeneration and deletion of its receptors does not extend regeneration unless activin receptors are also involved. 7, 8 Extracellular matrix (ECM) is inhibitory to proliferation of hepatocytes in culture. ECM is remodeled and partially degraded during regeneration and is gradually rebuilt at the end of regeneration. 1 Disruption of ECM signaling by hepatocyte-targeted elimination of integrin-linked kinase results in hepatic enlargement, decrease in hepatocyte ploidy, and increased deposition of ECM by stellate cells. PH in these mice terminates in a liver size much larger than the already larger-than-normal liver size observed before hepatectomy. 9, 10 Glypican-3 (GPC3), overexpressed in hepatocellular carcinomas, appears to be a growth suppressor for liver and hepatocytes. Expression of GPC3 increases toward the end of regeneration, and GPC3 transgenic mice have smaller livers at the end of regeneration than the initial size, Abbreviations: C/EBP, CCAAT-enhancer-binding protein; ECM, extracellular matrix; GPC3, glypican-3; GSK3b, glycogen synthase kinase 3 beta; HGF, hepatocyte …