Oxidative stress is a key factor in many diseases, including atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer. While many small molecules have shown therapeutic potential in preclinical studies, clinical trials have been disappointing. Understanding the mechanisms of antioxidant action and their limitations is crucial for developing effective therapies. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, are more effective than small molecules in removing oxidants. However, in extracellular fluids, mimics of these enzymes can be effective. Antioxidant therapy aims to enhance antioxidant defenses, which can be achieved through physiological signaling, dietary components, or pharmaceutical interventions. The review discusses the roles of oxidative stress in disease, the mechanisms through which it contributes to pathology, and the limitations of antioxidant therapies. It also highlights emerging approaches to modulate antioxidant defenses therapeutically. The article emphasizes the importance of understanding the mechanisms of oxidants and the limitations of antioxidant therapies to develop a rational approach for therapeutic intervention. Current clinical trials are exploring various antioxidant therapies, including SOD and catalase mimics, glutathione peroxidase (GPX) mimics, and other compounds. The review also discusses the challenges in targeting oxidative stress in diseases and the need for a better understanding of the mechanisms involved.Oxidative stress is a key factor in many diseases, including atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer. While many small molecules have shown therapeutic potential in preclinical studies, clinical trials have been disappointing. Understanding the mechanisms of antioxidant action and their limitations is crucial for developing effective therapies. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, are more effective than small molecules in removing oxidants. However, in extracellular fluids, mimics of these enzymes can be effective. Antioxidant therapy aims to enhance antioxidant defenses, which can be achieved through physiological signaling, dietary components, or pharmaceutical interventions. The review discusses the roles of oxidative stress in disease, the mechanisms through which it contributes to pathology, and the limitations of antioxidant therapies. It also highlights emerging approaches to modulate antioxidant defenses therapeutically. The article emphasizes the importance of understanding the mechanisms of oxidants and the limitations of antioxidant therapies to develop a rational approach for therapeutic intervention. Current clinical trials are exploring various antioxidant therapies, including SOD and catalase mimics, glutathione peroxidase (GPX) mimics, and other compounds. The review also discusses the challenges in targeting oxidative stress in diseases and the need for a better understanding of the mechanisms involved.