Nitric oxide (NO) is a gaseous signaling molecule in the biological system. It mediates its function through the direct modification of various cellular targets, such as through S-nitrosylation. The process of S-nitrosylation involves the attachment of NO to the cysteine residues of proteins. Interestingly, an increasing number of cellular pathways are found to be regulated by S-nitrosylation, and it has been proposed that this redox signaling pathway is comparable to phosphorylation in cells. However, imbalance of NO metabolism has also been linked to a number of human diseases. For instance, NO is known to contribute to neurodegeneration by causing protein nitration, lipid peroxidation and DNA damage. Moreover, recent studies show that NO can also contribute to the process of neurodegeneration through the impairment of pro-survival proteins by S-nitrosylation. Thus, further understanding of how NO, through S-nitrosylation, can compromise neuronal survival will provide potential therapeutic targets for neurodegenerative diseases.