Oxidative stress is a common mechanism of liver injury. Recent investigations have demonstrated that oxidant-induced liver injury is mediated by the direct effects of reactive oxygen species on signal transduction pathways. Although the function of cell signaling in this form of injury is complex and likely variable depending on the type and duration of oxidative stress, common regulatory pathways of hepatocyte oxidant injury have been identified that include the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 (ERK1/2) c-Jun N-terminal kinase (JNK), and the nuclear factor κB (NF-κB) pathway. Studies in cultured hepatocyte and rodent models of oxidative stress have demonstrated that ERK1/2 typically induces resistance to oxidant stress, whereas JNK promotes cell death. The effects of NF-κB activation are more complex and cell-type specific. A further understanding of the signaling pathways that regulate oxidant-induced liver injury may suggest new therapies for hepatic diseases resulting from oxidative stress.