Oxidative stress has been demonstrated to be a key pathogenic mechanism for the relatively selective degeneration of dopaminergic neurons in substantia nigra pars compacta seen in Parkinson's disease. But, it remains to be fully resolved how pathological features as widespread and generalized as oxidative stress can lead to cell-specific changes. This can potentially occur if specific cell-signalling pathways are triggered in response to oxidative stress only in certain cells, culminating in neuronal death. In this chapter, we discuss how dopaminergic neurons are more susceptible to oxidative stress and reactive oxygen species generation due to their cellular and molecular phenotype, and by putative mechanisms of redox-regulated repression of the Akt cell survival signalling pathway and activation of the ASK1 death signalling pathway. We present evidence from cell culture and animal models and in autopsy samples from Parkinson's disease patients. Future studies are needed to determine how these pathways interact with other Parkinson's disease associated pathological mechanisms to give us a more comprehensive understanding of the disease process.