Advances in our understanding of the etiologies and pathogenesis of Alzheimer's disease (AD) highlight a role for free radical-mediated injury to brain regions from early stages of this illness. Here we will review the evidence from transgenic mouse models of AD, autopsy samples, and human biofluids obtained during life paying particular attention to the stage of disease. In addition, we will review the epidemiologic literature that addresses the potential of anti-oxidants to prevent incident dementia from AD, and the clinical trial literature that addresses anti-oxidant preventative or therapeutic strategies for different stage of AD. Future efforts in preclinical models and ultimately clinical trials are needed to define optimally effective agents and combinations, doses, and timing to suppress safely this facet of AD.