Superoxide dismutase (SOD) is an antioxidative enzyme involved in the defense system against reactive oxygen species (ROS). SOD catalyzes the dismutation reaction of superoxide radical anion (O2-) to hydrogen peroxide, which is then catalyzed to innocuous O2 and H2O by glutathione peroxidase and catalase. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 184.108.40.206), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC 220.127.116.11), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 18.104.22.168), is the most recently characterized SOD, exists as a copper and zinc-containing tetramer. SOD3, which is highly expressed in selected tissues including blood vessels, heart, lungs, kidney and placenta, is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. SOD3 contains a unique heparin-binding domain at its carboxy-terminus that establishes localization to the extracellular matrix where the enzyme scavenges superoxide anion. SOD3 plays an important role in maintaining vascular tone, attenuating age-related cognitive decline, lung function, and the metabolism of NO, and in the pathology of such diseases as atherosclerosis, diabetes, and arthritis.