The Activator Protein 1 (AP‐1) transcription factor subunit Fos‐related antigen 1 (Fra‐1) has been implicated in liver fibrosis. Here we used loss‐of‐function as well as switchable, cell type‐specific, gain‐of‐function alleles for Fra‐1 to investigate the relevance of Fra‐1 expression in cholestatic liver injury and fibrosis. Our results indicate that Fra‐1 is dispensable in three well‐established, complementary models of liver fibrosis. However, broad Fra‐1 expression in adult mice results in liver fibrosis, which is reversible, when ectopic Fra‐1 is switched off. Interestingly, hepatocyte‐specific Fra‐1 expression is not sufficient to trigger the disease, although Fra‐1 expression leads to dysregulation of fibrosis‐associated genes. Both opn and cxcl9 are controlled by Fra‐1 in gain‐of‐function and loss‐of‐function experiments. Importantly, Fra‐1 attenuates liver damage in the 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine‐feeding cholestatic liver injury model. Strikingly, manipulating Fra‐1 expression affects genes involved in hepatic transport and detoxification, in particular glutathione S‐transferases. Molecular analyses indicate that Fra‐1 binds to the promoters of cxcl9 and gstp1 in vivo. Furthermore, loss of Fra‐1 sensitizes, while hepatic Fra‐1 expression protects from acetaminophen‐induced liver damage, a paradigm for glutathione‐mediated acute liver failure. Conclusion: These data define a novel function of Fra‐1/AP‐1 in modulating the expression of detoxification genes and the adaptive response of the liver to bile acids/xenobiotic overload. (Hepatology 2014;58:261–273)