In this study, we determined the role of the nuclear factor‐kappaB (NF‐κB) subunit c‐Rel in liver injury and regeneration. In response to toxic injury of the liver, c‐Rel null (c‐rel−/−) mice displayed a defect in the neutrophilic inflammatory response, associated with impaired induction of RANTES (Regulated upon Activation, Normal T‐cell Expressed, and Secreted; also known as CCL5). The subsequent fibrogenic/wound‐healing response to both chronic carbon tetrachloride and bile duct ligation induced injury was also impaired and this was associated with deficiencies in the expression of fibrogenic genes, collagen I and α‐smooth muscle actin, by hepatic stellate cells. We additionally report that c‐Rel is required for the normal proliferative regeneration of hepatocytes in response to toxic injury and partial hepatectomy. Absence of c‐Rel was associated with blunted and delayed induction of forkhead box M1 (FoxM1) and its downstream targets cyclin B1 and Cdc25C. Furthermore, isolated c‐rel−/− hepatocytes expressed reduced levels of FoxM1 and a reduced rate of basal and epidermal growth factor–induced DNA synthesis. Chromatin immunoprecipitation revealed that c‐Rel binding to the FoxM1 promoter is induced in the regenerating liver. Conclusion: c‐Rel has multiple functions in the control of liver homeostasis and regeneration and is a transcriptional regulator of FoxM1 and compensatory hepatocyte proliferation.