Dopaminergic neuronal cell loss in the substantia nigra pars compacta (SNpc) is considered the pathological hallmark of Parkinson’s disease (PD). Since the early 1990s, oxidative stress has been suggested to exert a causative role in the loss of dopaminergic cells. Post-mortem brain sample analyses have reported an increased accumulation of oxidized proteins, nucleic acids and lipids in PD brains. In this chapter, we will provide an introductory overview of reactive oxygen/nitrogen species, antioxidants, and oxidative modification to biomolecules, and the pathogenic mechanisms involved in the alteration of redox homeostasis that occurs in PD. We will also discuss the intrinsic properties of SNpc dopaminergic neurons that make them vulnerable to neurodegeneration. Energy failure and oxidative stress in PD are linked primarily to impaired mitochondria function (ETC), and both phenomena are expected to synergistically act to promote neuronal dysfunction and neurodegeneration. The high energy demands that SNpc DAergic neurons have to maintain neuronal homeostasis and excitability, and the pro-oxidant environment (iron/neuromelanin and dopamine content) are characteristics that make them primary targets for mitochondrial dysfunction.