The present review paper focuses on the chemistry of oxidative stress mitigation by antioxidants. Oxidative stress is understood as a lack of balance between the pro-oxidant and the antioxidant species. Reactive oxygen species in limited amounts are necessary for cell homeostasis and redox signaling. Excessive reactive oxygenated/nitrogenated species production, which counteracts the organism's defense systems, is known as oxidative stress. Sustained attack of endogenous and exogenous ROS results in conformational and oxidative alterations in key biomolecules. Chronic oxidative stress is associated with oxidative modifications occurring in key biomolecules: lipid peroxidation, protein carbonylation, carbonyl (aldehyde/ketone) adduct formation, nitration, sulfoxidation, DNA impairment such strand breaks or nucleobase oxidation. Oxidative stress is tightly linked to the development of cancer, diabetes, neurodegeneration, cardiovascular diseases, rheumatoid arthritis, kidney disease, eye disease. The deleterious action of reactive oxygenated species and their role in the onset and progression of pathologies are discussed. The results of oxidative attack become themselves sources of oxidative stress, becoming part of a vicious cycle that amplifies oxidative impairment. The term antioxidant refers to a compound that is able to impede or retard oxidation, acting at a lower concentration compared to that of the protected substrate. Antioxidant intervention against the radicalic lipid peroxidation can involve different mechanisms. Chain breaking antioxidants are called primary antioxidants, acting by scavenging radical species, converting them into more stable radicals or non-radical species. Secondary antioxidants quench singlet oxygen, decompose peroxides, chelate prooxidative metal ions, inhibit oxidative enzymes. Moreover, four reactivity-based lines of defense have been identified: preventative antioxidants, radical scavengers, repair antioxidants, and those relying on adaptation mechanisms. The specific mechanism of a series of endogenous and exogenous antioxidants in particular aspects of oxidative stress, is detailed. The final section resumes critical conclusions regarding antioxidant supplementation.