The article reviews the relationship between oxidative stress, redox signaling, and various diseases, focusing on the mechanisms by which oxidative stress contributes to pathology. It discusses how antioxidant defenses work, their limitations, and potential strategies to enhance them. Oxidative stress is an imbalance between the production of oxidants and the ability to prevent oxidative damage, leading to cellular damage. Redox signaling involves oxidants acting as second messengers, while antioxidant defenses prevent or repair oxidative damage. The article highlights the limitations of antioxidant therapy in clinical trials and emphasizes the need to understand where and when antioxidants are effective. It also reviews the mechanisms of oxidative stress, including the production of reactive oxygen species (ROS) and their role in diseases such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer. The article discusses current therapeutic approaches, including the use of superoxide dismutase (SOD) and glutathione peroxidase (GPX) mimics, and the activation of the NRF2 transcription factor. It concludes by emphasizing the importance of realistic expectations and targeted interventions to enhance antioxidant defenses effectively.The article reviews the relationship between oxidative stress, redox signaling, and various diseases, focusing on the mechanisms by which oxidative stress contributes to pathology. It discusses how antioxidant defenses work, their limitations, and potential strategies to enhance them. Oxidative stress is an imbalance between the production of oxidants and the ability to prevent oxidative damage, leading to cellular damage. Redox signaling involves oxidants acting as second messengers, while antioxidant defenses prevent or repair oxidative damage. The article highlights the limitations of antioxidant therapy in clinical trials and emphasizes the need to understand where and when antioxidants are effective. It also reviews the mechanisms of oxidative stress, including the production of reactive oxygen species (ROS) and their role in diseases such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer. The article discusses current therapeutic approaches, including the use of superoxide dismutase (SOD) and glutathione peroxidase (GPX) mimics, and the activation of the NRF2 transcription factor. It concludes by emphasizing the importance of realistic expectations and targeted interventions to enhance antioxidant defenses effectively.