Oxidative stress is associated with the onset and pathogenesis of several prominent central nervous system disorders. Consequently, there is a pressing need for experimental methods for studying neuronal responses to oxidative stress. A number of techniques for modeling oxidative stress have been developed, including the use of inhibitors of the mitochondrial respiratory chain, depletion of endogenous antioxidants, application of products of lipid peroxidation, use of heavy metals, and models of ischemic brain injury. These experimental approaches can be applied from cell culture to in vivo animal models. Their use has provided insight into the molecular underpinnings of oxidative stress responses in the nervous system, including cell recovery and cell death. Reactive oxygen species contribute to conformational change-induced activation of signaling pathways, inactivation of enzymes through modification of catalytic cysteine residues, and subcellular redistribution of signaling molecules. In this review, we will discuss several methods for inducing oxidative stress in the nervous system and explore newly emerging concepts in oxidative stress signaling.