Xenon is a rare noble gas that was introduced into clinical practice more than 70 years ago. Xenon's clinical properties are predicated by its ability to fit into preformed cavities of macromolecules thereby altering their biological functions. One such action targets the NMDA-subtype of the glutamate receptors thereby inhibiting its excitatory action. As the glutamate receptors are pivotal for both anesthesia and acute neurological injury, its clinical use has included both general anesthesia as well as neuroprotection. In this manuscript, the efficacy and safety of xenon in clinical trials that address both the anesthetic and neuroprotective applications are discussed. Because of the clinical safety of this chemically inert monatomic gas, the lack of an alternative for neuroprotection, and encouraging phase 2 trial data, a multinational pivotal randomized clinical trial (XePOHCAS) has been launched to assess the utility of xenon for patients that have been successfully resuscitated following an out of hospital cardiac arrest but still remain comatose, indicating ongoing neurological ischemic-perfusion injury. If successful, the trial will herald a new era of treatments for previously intractable conditions such as traumatic brain injury, ischemic and hemorrhagic strokes, and anesthetic-induced developmental neurotoxicity.