Considerable data support the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions, such as cell redox states and acute versus chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of mitochondrial deficits and a reduction in oxidative stress will reduce clinical and pathological changes and benefit patients.