Nitric oxide (NO) has been implicated in a large number of disease processes, including ischemia-reperfusion injury following the restoration of oxygenated blood to previously ischemic muscle, which is a recognized significant complication of vascular surgery. Altered metabolism of NO is implicated in the endothelial dysfunction that forms part of the pathophysiology of ischemia-reperfusion injury. However, NO can demonstrate either protective or cytotoxic effects during reperfusion injury. The use of transgenic mice, either NO synthase (NOS) gene knockout animals, or animals that over-express NOS isoforms, along with direct NO measurements and NO donor or inhibitor studies, have all demonstrated a role for NO in skeletal muscle reperfusion injury. There appears to be an initial stimulation of NO production in the first 20-min of ischemia, with a gradual decline through early reperfusion and a second higher peak of NO commencing in the later stages of reperfusion. The absolute levels of NO in the reperfused tissue and its regulation by the subtle interplay with superoxide and the subsequent production of the highly toxic peroxynitrite anion, are important factors in determining whether NO, in the context of ischemia-reperfusion injury, has damaging or protective effects in the body.