Activation of microglial cells and impaired mitochondrial function are common pathological characteristics of many neurological diseases and contribute to increased generation of reactive oxygen species (ROS). It is nowadays accepted that oxidative damage and mitochondrial dysfunction are key hallmarks of classical neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. To counteract the detrimental effects of ROS and restore the delicate redox balance in the central nervous system (CNS), cells are equipped with an endogenous antioxidant defense mechanism consisting of several antioxidant enzymes. The production of many antioxidant enzymes is regulated at the transcriptional level by the transcription factor nuclear factor E2-related factor 2 (Nrf2). Although evidence is accumulating that activation of the Nrf2 pathway represents a promising therapeutic approach to restore the CNS redox balance by reducing ROS-mediated neuronal damage in experimental models of neurodegenerative disorders, only a few Nrf2-activating compounds have been tested in a clinical setting. We here provide a comprehensive synopsis on the role of ROS in common neurodegenerative disorders and discuss the therapeutic potential of the Nrf2 pathway.