Background: The noble gases xenon and argon are neuroprotective in models of brain injury. This thesis investigated the neuroprotective mechanisms of the inert gases xenon, argon, krypton, neon and helium in in vitro models of traumatic brain injury and ischemia. Methods: This study used an in vitro model of focal mechanical trauma and oxygen and glucose deprivation using mouse organotypic hippocampal brain slices. Injury was quantified by propidium iodide fluorescence. Results: Xenon (50.6 kPa) and, to a lesser extent, argon (50.6 kPa) are neuroprotective against traumatic injury when applied after injury (xenon 0.43 ± 0.03 protection at 72 h after injury [N = 104]; argon 0.30 ± 0.0% protection [N = 44] vs control injury 1.0 ± 0.05 [N=144]; mean ± SEM). Helium, neon, and krypton are devoid of neuroprotective effect. Xenon (50.6 kPa) prevents development of secondary injury after trauma. Argon (50.6 kPa) attenuates secondary injury, but is less effective than xenon (xenon 0.50 ± 0.05 reduction in secondary injury at 72 h after injury [N = 104]; argon 0.34 ± 0.08 reduction [N = 44] vs control 0.86 ± 0.05 [N = 144]; mean ± SEM). Glycine reverses the neuroprotective effect of xenon, but not argon in both models of TBI and OGD, consistent with competitive inhibition at the N-methyl-d-aspartate receptor glycine site mediating xenon neuroprotection against traumatic brain injury. Conclusions: Xenon neuroprotection against traumatic and ischemic brain injury can be reversed by elevated concentrations of glycine, indicating a key role of inhibition of the NMDA receptor glycine co-agonist site in mediating neuroprotection against these injuries. Argon does not appear to have any effects on NMDA receptors and is neuroprotective via a mechanism distinct to that of xenon. Krypton and neon are devoid of neuroprotective effects in either injury model.