Oleanolic acid (OA) is a natural triperpenoid that protects against a variety of hepatotoxicants such as carbon tetrachloride, cadmium, acetaminophen, and bromobenzene. To gain insight into the molecular mechanisms of this generalized hepatoprotection, genomic analysis was performed on mouse and rat livers after OA treatment. Mice and rats were given OA at a hepatoprotective dose (50 micromol/kg, s.c., daily for 4 days) and hepatic RNA was isolated, purified, and subjected to gene expression analysis. OA treatment produced changes in 5% of the genes on custom-designed mouse liver array and rat toxicology-II array. Changes in key gene expressions were further analyzed by real-time RT-PCR. OA treatment dramatically increased expression of hepatic metallothionein (Mt), and increased the expression of the nuclear factor E2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (Nqo1), heme oxygenase-1 (Hmox1), and glutamate-cysteine ligases (Gclc and Gclm). OA treatment also increased the expression of genes related to cell proliferation and suppressed the expression of several cytochrome P450 genes possibly to switch cellular metabolic energy to an acute-phase response. Hepatic MT protein was increased 60- and 15-fold in mice and rats, respectively, together with a 30% increase in mouse liver zinc. These gene expression changes, particularly the dramatic induction of MT and the Nrf2 signaling, occur with hepatoprotection doses of OA, and likely are important in the generalized protective effects of OA against hepatotoxicants.