Atherosclerosis is a complex fibroproliferative-inflammatory process triggered by vascular injury. Transcription factors play an important role in the control of genes that effect critical changes in the vessel wall. Recent evidence indicates an emerging role for activation transcription factor 4 (ATF4), a master regulator for evolutionarily conserved mammalian stress response pathways, in cardiovascular pathologic settings. For example, in endothelial cells, ATF4 is induced by atherogenic factors such as oxidised phospholipids and homocysteine, and in monocytes, ATF4 is activated by hypoxia. In this context, ATF4 is thought to regulate pro-inflammatory signalling cascades and subsequent apoptosis. ATF4 is induced in aortic smooth muscle cells by fibroblast growth factor 2 and in the intact vessel wall following balloon angioplasty. Our own work indicates that ATF4 knockdown blocks injury-inducible intimal proliferation. Furthermore, studies in ATF4-deficient mice have established a role for ATF4 in diet-induced diabetes and hyperlipidaemia. In this article, we will review recent developments on the regulation of this intriguing nuclear protein and its transcriptional roles in the context of vascular injury and related disease.