Ketamine is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor which also interacts with various other receptors that account for its myriad actions. Originally approved as a general anesthetic, it is being explored to be repurposed for numerous other indications such as depressive disorders, suicidal ideation, substance-use disorders, anxiety disorders, chronic pain, refractory status epilepticus, and bronchial asthma exacerbations. Numerous trials are ongoing for the same. The nasal spray of esketamine, a more potent S (+) enantiomer of ketamine, has been approved by the United States Food and Drug Administration (USFDA) for treatment-resistant depression along with the oral antidepressants. However, there are concerns about its safety on long term use, given its psychedelic effects and potential abuse. In this review, we discuss repurposing ketamine for potential therapeutic use and about the safety concerns related to ketamine and esketamine.