Oxidative stress and excitotoxic injury are commonly associated with several neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and periventricular leukomalacia. As cystine is imported into the cell, it is used in the synthesis of intracellular glutathione, an important antioxidant necessary for the defense of brain cells from oxidative stress and glutamate-mediated excitotoxicity. Recent studies have shown that retinoic acid increases the activity of glutathione synthesis and exhibits neuroprotective properties in brain cells. Previously, we have shown that the regulation of the cystine glutamate exchanger (system Xc-) also leads to neuroprotection. Here, we examined the effects of retinoic acid on the regulation of system Xc-. Our results suggest that retinoic acid-induced neuroprotection is mediated through system Xc- by regulating glutathione biosynthesis. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.