Parkinson's disease (PD) is a common neurodegenerative disorder characterized by motor symptoms and progressive disability. Oxidative stress has been hypothesized to play a role in both the initiation and progression of PD. Pre-clinical studies using in vitro and in vivo models of PD suggest that the neurodegenerative process begins with healthy neurons being damaged by etiological factors, leading to a cascade of detrimental events. In these models, initial molecular alterations in dopaminergic neurons include increased formation of reactive oxygen species (ROS), which may originate from both inside and outside the mitochondria. In the MPTP mouse model of PD, time-course experiments indicate that oxidative stress is an early event that may directly kill some dopaminergic neurons. Additionally, oxidative stress may indirectly contribute to neuronal death by activating intracellular cell death-related pathways. As the neurodegenerative process progresses, indices of neuroinflammation develop, such as microglial activation, which increases the oxidative stress experienced by neighboring compromised neurons, promoting their demise. However, these experimental studies also show that oxidative stress is not the sole factor contributing to dopaminergic neuron death. If a similar multifactorial cascade underlies dopaminergic neuron degeneration in PD, then effective therapy may require a cocktail of agents targeting different critical components of this hypothesized pathogenic cascade. This may explain why single-agent neuroprotective trials using antioxidants have generally been disappointing.Parkinson's disease (PD) is a common neurodegenerative disorder characterized by motor symptoms and progressive disability. Oxidative stress has been hypothesized to play a role in both the initiation and progression of PD. Pre-clinical studies using in vitro and in vivo models of PD suggest that the neurodegenerative process begins with healthy neurons being damaged by etiological factors, leading to a cascade of detrimental events. In these models, initial molecular alterations in dopaminergic neurons include increased formation of reactive oxygen species (ROS), which may originate from both inside and outside the mitochondria. In the MPTP mouse model of PD, time-course experiments indicate that oxidative stress is an early event that may directly kill some dopaminergic neurons. Additionally, oxidative stress may indirectly contribute to neuronal death by activating intracellular cell death-related pathways. As the neurodegenerative process progresses, indices of neuroinflammation develop, such as microglial activation, which increases the oxidative stress experienced by neighboring compromised neurons, promoting their demise. However, these experimental studies also show that oxidative stress is not the sole factor contributing to dopaminergic neuron death. If a similar multifactorial cascade underlies dopaminergic neuron degeneration in PD, then effective therapy may require a cocktail of agents targeting different critical components of this hypothesized pathogenic cascade. This may explain why single-agent neuroprotective trials using antioxidants have generally been disappointing.