Hepatocyte growth factor (HGF)/c‐Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c‐Met in stem‐cell–mediated liver regeneration by utilizing mice harboring c‐met floxed alleles and Alb‐Cre or Mx1‐Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3,5‐diethocarbonyl‐1,4‐dihydrocollidine (DDC). Deletion of c‐met in oval cells was confirmed in both models by polymerase chain reaction analysis of fluorescence‐activated cell‐sorted epithelial cell adhesion molecule (EpCam)‐positive cells. Loss of c‐Met receptor decreased the sphere‐forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration, and decreased hepatocytic differentiation in vivo, as demonstrated by double immunofluorescence using oval‐ (A6 and EpCam) and hepatocyte‐specific (i.e. hepatocyte nuclear factor 4‐alpha) antibodies. Furthermore, lack of c‐Met had a profound effect on tissue remodeling and overall composition of HSC niche, which was associated with greatly reduced matrix metalloproteinase (MMP)9 activity and decreased expression of stromal‐cell–derived factor 1. Using a combination of double immunofluorescence of cell‐type–specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC‐treated livers. The Mx1‐Cre‐driven c‐met deletion caused the greatest phenotypic impact on HSCs response, as compared to the selective inactivation in the epithelial cell lineages achieved in c‐Met^fl/fl; Alb‐Cre^+/− mice. However, in both models, genetic loss of c‐met triggered a similar cascade of events, leading to the failure of HSC mobilization and death of the mice. Conclusion: These results establish a direct contribution of c‐Met in the regulation of HSC response and support a unique role for HGF/c‐Met as an essential growth‐factor–signaling pathway for regeneration of diseased liver. (HEPATOLOGY 2012)