There is widespread recognition that reactive oxygen species (ROS) play key roles in normal brain function and pathology in the context of neurological disease. Oxidative stress continues to be a key therapeutic target for neurological diseases. In developing antioxidant therapies for neurological disease, special attention should be given to the brain's unique vulnerability to oxidative insults and its architecture. Consideration of antioxidant therapy should be guided by a strong rationale for oxidative stress in a given neurological disease. This review provides an overview of processes that can guide the development of antioxidant therapies in neurological diseases, such as knowledge of basic redox mechanisms, unique features of brain pathophysiology, mechanisms and classes of antioxidants, and desirable properties of drug candidates.