Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of antioxidant/detoxifying enzymes. To understand the molecular basis of NRF2-mediated protection against oxidative lung injury, pulmonary gene expression profiles were characterized in Nrf2-disrupted (Nrf2^−/−) and wild-type (Nrf2^+/+) mice exposed to hyperoxia or air. Genes expressed constitutively higher in Nrf2^+/+ mice than in Nrf2^−/− mice included antioxidant defense enzyme and immune cell receptor genes. Higher basal expression of heat shock protein and structural genes was detected in Nrf2^−/− mice relative to Nrf2^+/+ mice. Hyperoxia enhanced expression of 175 genes (≥ twofold) and decreased expression of 100 genes (≥50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g., Txnrd1, Ex, Cp-2) and other novel genes (e.g., Pkc-α, Tcf-3, Ppar-γ) was markedly greater in Nrf2^+/+ mice than in Nrf2^−/− mice. In contrast, induced expression of genes encoding extracellular matrix and cytoskeletal proteins was higher in Nrf2^−/− mice than in Nrf2^+/+ mice. These NRF2-dependent gene products might have key roles in protection against hyperoxic lung injury. Results from our global gene expression profiles provide putative downstream molecular mechanisms of oxygen tissue toxicity.