Besides the genetic, biochemical and neuropathological analogies between Down's syndrome (DS) and Alzheimer's disease (AD), there is ample evidence of the involvement of oxidative stress (OS) in the pathogenesis of both disorders. The present paper reviews the publications on DS and AD in the past 10 years in light of the "gene dosage" and "two-hit" hypotheses, with regard to the alterations caused by OS in both the central nervous system and the periphery, and the main pipeline of antioxidant therapeutic strategies. OS occurs decades prior to the signature pathology and manifests as lipid, protein and DNA oxidation, and mitochondrial abnormalities. In clinical settings, the assessment of OS has traditionally been hampered by the use of assays that suffer from inherent problems related to specificity and/or sensitivity, which explains some of the conflicting results presented in this work. For DS, no scientifically proven diet or drug is yet available, and AD trials have not provided a satisfactory approach for the prevention of and therapy against OS, although most of them still need evidence-based confirmation. In the future, a balanced up-regulation of endogenous antioxidants, together with multiple exogenous antioxidant supplementation, may be expected to be one of the most promising treatment methods.