Esketamine, the only intranasal (IN) antidepressant approved by the FDA and EMA for therapy of treatment-resistant depression (TRD) has demonstrated significant depressive symptom reduction in short-term, randomized, placebo-controlled study. It induced superior remission rates compared to extended-release quetiapine after week 8 of therapy in TRD as well. Providing rapid onset of action post-administration, its efficacy can be sustained with repeated use. Long-term study also indicates increased rates of response and remission, with reduced risk of relapse. Real-world observational data corroborate these findings, showing significant symptom improvement at various time points after IN esketamine therapy. In general, IN esketamine has been well tolerated, with mild to moderate adverse events resolving within hours of administration. This chapter narratively reviews available evidence of the efficacy and safety of IN esketamine as well as important considerations for clinical practice when applied as therapy for TRD.