Manganese (Mn) is a ubiquitous and essential element that can be toxic at high doses. In individuals exposed to high levels of this metal, Mn can accumulate in various brain regions, leading to neurotoxicity. In particular, Mn accumulation in the mid-brain structures, such as the globus pallidus and striatum, can lead to a Parkinson's-like movement disorder known as manganism. While the mechanism of this toxicity is currently unknown, it has been postulated that Mn may be involved in the generation of reactive oxygen species (ROS) through interaction with intracellular molecules, such as superoxide and hydrogen peroxide, produced within mitochondria. Conversely, Mn is a required component of an important antioxidant enzyme, Mn superoxide dismutase (MnSOD), while glutamine synthetase (GS), a Mn-containing astrocyte-specific enzyme, is exquisitely sensitive to oxidative stress. To investigate the possible role of oxidative stress in Mn-induced neurotoxicity, a series of inhalation studies was performed in neonatal and adult male and female rats as well as senescent male rats exposed to various levels of airborne-Mn for periods of time ranging from 14 to 90 days. Oxidative stress was then indirectly assessed by measuring glutathione (GSH), metallothionein (MT), and GS levels in several brain regions. MT and GS mRNA levels and regional brain Mn concentrations were also determined. The collective results of these studies argue against extensive involvement of ROS in Mn neurotoxicity in rats of differing genders and ages. There are, however, instances of changes in individual endpoints consistent with oxidative stress in certain brain tissues.