Research over the past years has compared the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine) of the previously known racemic mixture called ketamine (R/S-ketamine). Esketamine has been found to be more potent, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy than arketamine. It provides smoother anesthesia with fewer side effects and is widely used in clinical settings due to its neuroprotective, bronchodilatory, and antiepileptic properties. Approved by the FDA and EMA in 2019, esketamine is currently used alongside SSRIs or SNRIs for treatment-resistant depression (TRD). On the other hand, arketamine has shown potential for treating neurological disorders such as Alzheimer’s, Parkinson’s, and multiple sclerosis, offering possible antidepressant effects and anti-inflammatory benefits. While esketamine is already in clinical use, arketamine’s future depends on further research to address its safety, efficacy, and optimal dosing. Both enantiomers hold significant clinical value, with esketamine excelling in anesthesia, and arketamine showing promise in neurological and psychiatric treatments.