The generation of reactive oxygen species and subsequent oxidative stress in the central nervous system is now considered to be one of the primary etiologies of a host of neurodegenerative disorders, such as Alzheimer disease, Parkinson disease, and cerebral ischemia. On a cellular level, oxidative stress leads to an apoptotic early phase that involves cellular membrane phosphatidylserine (PS) exposure and a late phase that pertains to the degradation of genomic DNA. The translocation of membrane PS from the inner cellular membrane to the surface is a critical component for both microglial activation and cellular disposal of injured cells. During oxidative stress, this early phase of apoptosis is intimately controlled by neuronal PS exposure and microglial PS receptor expression. The late phase of apoptosis that involves a loss of genomic DNA integrity can result as a function of an ill-fated attempt to enter the cell cycle in postmitotic neurons. By using a cascade of pathways that involve cysteine proteases to modulate programmed cell death, protein kinase B (Akt) surfaces as a key regulatory element of both extrinsic pathways of inflammation and intrinsic pathways of cellular integrity. Further understanding of the cellular mechanisms modulating neuronal cellular integrity and phagocytic cell disposal during oxidative stress may form the basis for the future development of cytoprotective strategies in the nervous system.