Superoxide dismutases (SODs) are key antioxidant enzymes that play critical roles in redox signaling, vascular function, and the prevention of oxidative stress-related diseases. SODs catalyze the conversion of superoxide anion (O₂⁻) to hydrogen peroxide (H₂O₂), which can then be further metabolized to water. There are three main SOD isoforms in mammals: SOD1 (cytoplasmic Cu/ZnSOD), SOD2 (mitochondrial MnSOD), and SOD3 (extracellular Cu/ZnSOD). Each SOD isoform is localized to specific subcellular compartments and plays distinct roles in maintaining redox homeostasis. SOD1 is primarily found in the cytosol and mitochondria, and its activity is dependent on copper (Cu) ions. SOD2 is located in the mitochondrial matrix and requires manganese (Mn) for its function. SOD3 is secreted into the extracellular space and is anchored to the extracellular matrix via heparan sulfate proteoglycans. SOD3 is particularly important in the vascular extracellular space, where it helps to prevent the inactivation of nitric oxide (NO) by superoxide radicals, thereby maintaining NO-mediated signaling. SODs are essential for protecting against oxidative stress, which is implicated in various cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. SODs also play a role in regulating redox signaling pathways, which are crucial for vascular function, inflammation, and angiogenesis. The activity of SODs is dependent on the availability of their respective metal cofactors (Cu or Mn), which are delivered to the enzymes through specific chaperone proteins. Recent studies have shown that SODs are involved in various physiological and pathological processes, including the regulation of NO signaling, mitochondrial function, and the prevention of superoxide-induced cytotoxicity. SOD1, SOD2, and SOD3 have distinct roles in these processes, with SOD1 primarily involved in cytosolic and mitochondrial redox signaling, SOD2 in mitochondrial function, and SOD3 in extracellular redox signaling and NO protection. The importance of SODs in cardiovascular disease has led to increased interest in antioxidant therapies that aim to enhance endogenous antioxidant defenses. However, clinical evidence regarding the efficacy of such therapies remains controversial. Future research should focus on understanding the mechanisms by which SODs obtain their catalytic metal cofactors and on developing SOD-dependent therapeutic strategies to treat oxidative stress-related diseases.Superoxide dismutases (SODs) are key antioxidant enzymes that play critical roles in redox signaling, vascular function, and the prevention of oxidative stress-related diseases. SODs catalyze the conversion of superoxide anion (O₂⁻) to hydrogen peroxide (H₂O₂), which can then be further metabolized to water. There are three main SOD isoforms in mammals: SOD1 (cytoplasmic Cu/ZnSOD), SOD2 (mitochondrial MnSOD), and SOD3 (extracellular Cu/ZnSOD). Each SOD isoform is localized to specific subcellular compartments and plays distinct roles in maintaining redox homeostasis. SOD1 is primarily found in the cytosol and mitochondria, and its activity is dependent on copper (Cu) ions. SOD2 is located in the mitochondrial matrix and requires manganese (Mn) for its function. SOD3 is secreted into the extracellular space and is anchored to the extracellular matrix via heparan sulfate proteoglycans. SOD3 is particularly important in the vascular extracellular space, where it helps to prevent the inactivation of nitric oxide (NO) by superoxide radicals, thereby maintaining NO-mediated signaling. SODs are essential for protecting against oxidative stress, which is implicated in various cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. SODs also play a role in regulating redox signaling pathways, which are crucial for vascular function, inflammation, and angiogenesis. The activity of SODs is dependent on the availability of their respective metal cofactors (Cu or Mn), which are delivered to the enzymes through specific chaperone proteins. Recent studies have shown that SODs are involved in various physiological and pathological processes, including the regulation of NO signaling, mitochondrial function, and the prevention of superoxide-induced cytotoxicity. SOD1, SOD2, and SOD3 have distinct roles in these processes, with SOD1 primarily involved in cytosolic and mitochondrial redox signaling, SOD2 in mitochondrial function, and SOD3 in extracellular redox signaling and NO protection. The importance of SODs in cardiovascular disease has led to increased interest in antioxidant therapies that aim to enhance endogenous antioxidant defenses. However, clinical evidence regarding the efficacy of such therapies remains controversial. Future research should focus on understanding the mechanisms by which SODs obtain their catalytic metal cofactors and on developing SOD-dependent therapeutic strategies to treat oxidative stress-related diseases.