Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide‐dependent protein kinase 1 (PDK1)‐associated pathways in liver regeneration after partial hepatectomy (PH) using liver‐specific Pdk1‐knockout (L‐Pdk1KO) and Pdk1/STAT3 double KO (L‐DKO) mice. There was no liver regeneration, and 70% PH was lethal in L‐Pdk1KO mice. Liver regeneration was severely impaired equally in L‐Pdk1KO and L‐DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L‐Pdk1KO mice, although the post‐PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt‐phosphorylation (Thr308) in L‐Pdk1KO mice, and post‐PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (p70^S6K), and S6 were also reduced. To examine the specific role of PDK1‐associated signals, a “pif‐pocket” mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used. Liver regeneration was recovered in L‐Pdk1KO mice with a “pif‐pocket” mutant of PDK1. This re‐activated Akt in L‐Pdk1KO mice liver and induced post‐PH cell growth, without affecting cell proliferation. Further deletion of STAT3 (L‐DKO mice) did not further deteriorate liver regeneration, although this certainly reduced post‐PH mitotic response. These findings indicate that PDK1/Akt contribute to liver regeneration by regulating cell size. Regarding phosphatidylinositol‐3 kinase (PI3‐K), immediate upstream signal of PDK1, activation of PI3‐K induced cell proliferation via STAT3 activation in the liver of L‐Pdk1KO mice but did not improve impaired liver regeneration. This confirmed the pivotal role of PDK1 in liver regeneration and cell growth. Conclusion: PDK1/Akt‐mediated responsive cell growth is essential for normal liver regeneration after PH, especially when cell proliferation is impaired. (HEPATOLOGY 2009;49:204‐214.)