Cardiovascular disease is the most common cause of mortality in the Western world and accounts for up to a third of all deaths worldwide. Cardiovascular disease is multifactorial and involves complex interplay between lifestyle (diet, smoking, exercise, ethanol consumption) and fixed (genotype, age, menopausal status, gender) causative factors. The initiating step in cardiovascular disease is endothelial damage, which exposes these cells and the underlying cell layers to a deleterious inflammatory process which ultimately leads to the formation of atherosclerotic lesions. Intrinsic to lesion formation is cellular oxidative stress, due to the production of damaging free radicals (reactive oxygen and nitrogen species) by many cell types including endothelial cells, vascular smooth muscle cells and monocytes/macrophages. Exogenous factors such as smoking and the existence of other disease states such as diabetes also contribute to oxidative stress and are strong risk factors for cardiovascular disease. In this review we describe this role of free radicals in atherosclerosis and discuss the mechanisms and cellular systems by which these radicals are produced. We also highlight recent technological advances which have added to the vascular biologist's armoury and which promise to provide new insight into the role of reactive oxygen species in cardiovascular disease.