This chapter reviews recent preclinical studies on ketamine, emphasizing its dose- and context-dependent effects and important clinical implications. In the context of equimolar and / or equipotent dose, subanesthetic dose ketamine and its enantiomers are compared at first. Equimolar subanesthetic S-ketamine induces stronger psychomotor effects than racemic and R-ketamine in rats; repeated uses result in locomotor sensitization and tolerance to ataxic effects. In rodents, ketamine increases synaptic plasticity, prosocial behavior, and memory reconsolidation indicating therapeutic potential. In models of Parkinson’s disease and brain trauma, ketamine exerts neuroprotective effects reducing dyskinesia and cognitive impairment. Exposure to high-dose ketamine results in significant brain alterations including oscillatory gene regulation patterns with rebound activities during recovery from prolonged ketamine mono-anesthesia. This may be relevant in postoperative neurocognitive disorders. Repeated ketamine anesthesia induces the disassembly of perineuronal nets, which can reactivate juvenile-like plasticity. Ketamine may thus offer innovative approaches to brain recovery after injury. This research can be of significant translational value, particularly in the treatment of chronic neuropsychiatric conditions, perioperative anesthesia care, and neuroprotection and brain recovery.