Liver regeneration proceeds under the well-orchestrated control of multiple transcription factors that lead hepatocytes to reenter the cell cycle, proliferate, and renew quiescence. Here, we found an important role of the zinc-finger transcription factor Snail in liver regeneration. Snail was typically expressed in quiescent adult hepatocytes, but was rapidly degraded when the liver needed to regenerate itself. Decreased levels of Snail induced DNA synthesis in hepatocytes through up-regulation of cell cycle-related proteins. Snail degradation was dependent on phosphorylation by glycogen synthase kinase (GSK)-3β, whose quantity and activity were immediately increased after loss of liver mass or hepatic injury. Inactivation of GSK-3β resulted in suppression of Snail degradation and DNA synthesis in hepatocytes, leading to impaired liver growth during regeneration. This GSK-3β-dependent Snail degradation occurred as a result of cytokine, growth factor, and bile acid signals that are known to drive liver regeneration. Thus, GSK-3β-dependent Snail degradation acts as a fundamental cue for the initiation of hepatocyte proliferation in liver regeneration.