Oxidant stress [ OS ] is a condition in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen called reactive oxygen species [ROS], principal amongst which is superoxide [O2 -]. It is becoming increasingly apparent that O2 - is a key risk factor for cardiovascular disease [CVD], including atherogenesis, reperfusion injury, angina, restenosis following balloon angioplasty and vein graft failure. When one considers the multiplicity of effects of O2 -, this is perhaps not surprising, as it promotes vascular smooth muscle cell proliferation, damages the endothelium, promotes lipid oxidation and activates blood cells. However, perhaps the key reaction of O2 - is that with nitric oxide [NO] to form peroxynitrite [ONOO] resulting in a depletion of endogenous vascular NO. Reduced NO formation is also now firmly associated with the aetiology of CVD and as such NO donors may become a major class of drugs. Furthermore, risk factors for CVD, in particular diabetes mellitus [DM], dyslipidaemia, and hyperhomocysteinaemia are all associated with OS. As such, it is becoming increasingly apparent that novel antioxidant therapies, including the gene transfer of antioxidant enzymes, are potentially valuable in the treatment of CVD. In this review, the aetiology of OS and CVD is discussed with particular emphasis on NO. The interactions of risk factors and how this pathophysiology relates to the design of effective novel strategies to treat CVD is also considered. Particular emphasis is also placed on OS and cardiovascular surgery.