An unfortunate consequence of high metabolism in the brain is the age-related increase in oxidative stress observed. Multiple lines of evidence indicate that oxidative stress is one of the earliest events in Alzheimer disease, occurring before the development of plaques and tangles. The large number of metabolic signs of oxidative stress and markers of oxidative damage suggest that oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer disease. However, although long-lived markers of oxidative damage persist throughout the disease, the levels of rapidly turned over markers of oxidative damage, i.e., oxidized nucleic acids, which are initially elevated, decrease as the disease progresses to advanced Alzheimer disease indicating that oxidative stress decreases with disease progression. Thus, the initial burst of reactive oxygen species not only results in damage to cellular structures but also engenders a cellular response(s), i.e., the compensatory up-regulation of antioxidant enzymes found in vulnerable neurons in Alzheimer disease. In addition, oxidative stress also stimulates the stress-activated protein kinase pathways, which are extensively activated during Alzheimer disease. In this chapter, we review the evidence of oxidative stress and compensatory responses in Alzheimer disease and conclude with a focus mechanism of activation of stress-activated protein kinase pathways and the role of this pathway in the disease process.