Abstract: Oxidative stress has long been implicated as a driving force in neurodegenerative disease, with studies of human brain tissue and animal models revealing its important role. Parkinson’s disease (PD), in particular, highlights the selective vulnerability of neurons to the insults of reactive oxygen species. The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra. These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism (Watanabe et al., 2024). Glutathione, specifically in its reduced state (GSH), is a primary antioxidant whose deficiency has been implicated in PD and other neurodegenerative diseases (Bjørkland et al., 2021). The demonstrated neuroprotective effects of glutathione replenishment in animal PD models are at odds with less conclusive results in human clinical trials. This perspective piece outlines some of this preclinical and clinical evidence and proposes a way forward considering discrepancies between the human and animal data.