The aldehyde 4-hydroxy-2-nonenal (HNE) is an end-product of polyunsaturated fatty acid oxidation. HNE is involved in the pathogenesis of coronary artery disease and is present in oxidatively modified low density lipoproteins and in atherosclerotic plaques in humans. HNE enhances chronic inflammation within the vessel wall by activating macrophages, stimulates smooth muscle cell proliferation and fibrosis and contributes to endothelial cell dysfunction. Endogenous adaptive antioxidant pathways are activated in response to oxidative injury elicited by 4-HNE. The induction of antioxidant genes such as heme oxygenase-1 (HO-1) is co-ordinated by activation of mitogen-activated protein kinase pathways, leading to nuclear translocation of the transcription factor Nrf2 and subsequent transactivation of an antioxidant response element in the promoter regions of these genes. We here review the evidence that HNE activates Nrf2 and antioxidant gene expression in vascular and other cells types, highlighting the potential of targeting the Nrf2 as a therapeutic strategy for the prevention of vascular diseases characterised by oxidative injury and diminished antioxidant defence.