Some form of oxidative imbalance or damage is a part of the pathophysiology for all neurodegenerative diseases. Vitamin C has received significant attention for its potential ability to protect against oxidative damage in multiple neurodegenerative diseases including Alzheimer disease, Huntington disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. This chapter focuses on mechanisms of damage that can result from low vitamin C in the brain in addition to the contribution to global oxidative stress including mitochondrial dysfunction and glutamatergic excitotoxicity. We also discuss the evidence supporting the need to maintain high vitamin C levels during both normal aging and in individuals with, or who are at risk for, neurodegenerative disease, as well as the limitations of these studies.