An intranasal formulation of esketamine, the S enantiomer of ketamine, in conjunction with an oral antidepressant, has been approved by the FDA for treating treatment-resistant major depressive disorder (TRD) in 2019, almost 50 years after it was approved as an intravenous anesthetic. In contrast to traditional antidepressants, ketamine shows a rapid (within 2 h) and sustained (∼7 days) antidepressant effect and has significant positive effects on antisuicidal ideation. Ketamine's antidepressant mechanism is predominantly mediated by the N-methyl-d-aspartate receptor (NMDA) receptor, although NMDA-independent mechanisms are not ruled out. At the neurocircuitry level, ketamine affects the brain's reward and mood circuitry located in the corticomesolimbic structures involving the hippocampus, nucleus accumbens, and prefrontal cortex. Repurposing of ketamine for treating TRD provided a new understanding of the pathophysiology of depression, a paradigm shift from monoamine to glutamatergic neurotransmission, thus making it a unique tool to investigate the brain and its complex neurocircuitries.