The recent three decades emphasized research on liver regeneration, which focused on signals leading hepatocytes into proliferation and liver into regeneration. Mitogenic growth factors (ligands of EGFR and HGF) were identified as direct mitogens for both hepatocyte cultures as well as whole animals in vivo. Multiple other signals (including norepinephrine, IL6, TNF, bile acids, etc.) also initiate signaling pathways that streamline and optimize signaling pathways inside hepatocytes so that hepatocytes enter into cell cycle and proceed with DNA synthesis. Hepatocytes in the cell cycle generate paracrine signals to other hepatic cell types, producing GM-CSF (affecting Kupffer cells), VEGF-A and Angiopoietins 1 and 2 (affecting endothelial cells that themselves also produce HGF), TGFα and FGF1 (affecting a variety of cell types including hepatocytes themselves). Non-parenchymal cells in the liver also produce an array of mitogenic signaling molecules, including HGF (from stellate cells and endothelial cells), IL6 and TNF (from Kupffer cells). TGFβ1, considered as being produced primarily by stellate cells, does not appear to exert mito-inhibitory effects on regenerating hepatocytes, primarily due to down-regulation of TGFβ receptors during regeneration. Functions served by TGFβ during regeneration are more probably related to control of synthesis of hepatic biomatrix, which is substantially downgraded and remodeled during the early stages of regeneration and is resynthesized towards the end of the process [1]. Much less attention has been paid to the pathways leading to cessation of regeneration. It is remarkable that at the end of regeneration, liver returns to 100% of the original mass, suggesting the presence of a “hepatostat” correlating liver size to body size and function. Crucial to understanding this system is the understanding of the signaling pathways leading to proper termination of liver regeneration, as it is this phase of the process that guarantees return to the original size. Many studies with a variety of epithelial cell types have shown elimination of growth suppressing signals in neoplastic development. Cancer tissues proceed with continual proliferation, due to elimination of internal checkpoints and cell cycle control systems. In this study, we concentrated on several systems apparently associated with termination of liver regeneration and demonstrated that such systems are either non-functional or eliminated in hepatocellular carcinomas (HCC). Conversely, by applying detailed genomic analysis, we also found specific genes deleted in the majority or in many hepatocellular carcinomas whose function, not apparent at first, appears to relate with growth suppressor signals associated with termination or negative control of liver regeneration. Such signals related to the present study are as follows: