Athero-thrombosis of the arteries supplying the brain and lower limb are the main causes of stroke and limb loss. New therapies are needed to improve the outcomes of athero-thrombosis. Recent evidence suggests a role for epigenetic changes in the development and progression of ischaemic injury due to atherosclerotic occlusion of peripheral arteries. DNA hypermethylation have been associated with cardiovascular diseases. Histone post-translational modifications have also been implicated in atherosclerosis. Oxidized low-density lipoprotein regulated pro-inflammatory gene expression within endothelial cells is controlled by phosphorylation/acetylation of histone H3 and acetylation of histone H4 for example. There are a number of challenges in translating the growing evidence implicating epigenetics in atherosclerosis to improved therapies for patients. These include the small therapeutic window in conditions such as acute stroke and critical limb ischaemia, since interventions introduced in such patients need to act rapidly and be safe in elderly patients with many co-morbidities. Pre-clinical animal experiments have also reported conflicting effects of some novel epigenetic drugs, which suggest that further in-depth studies are required to better understand their efficacy in resolving ischaemic injury. Effective ways of dealing with these challenges are needed before epigenetic approaches to therapy can be introduced into practice.