Nitric oxide/peroxynitrite signaling is associated with manifold neurovascular pathogenic cascades that lead to neurodegenerative diseases, including ischemic stroke, Alzheimer's disease, and vascular dementia. Considerable evidence suggests that reactive nitrogen species as mediators of nitrosative stress could damage biomolecules and subsequently facilitate the breakdown of the highly-structured cellular machinery. Herein, we focus on nitrosative stress signaling, which is intimately associated with endothelial cell injury and blood-brain barrier damage in stroke and neurodegenerative diseases. Unraveling the detrimental role of nitrosative stress signaling in initiating and driving neurovascular pathogenesis may lead to the development of novel vasoprotective strategies via restorative therapies for brain diseases.