The approval of intranasal esketamine for treatment-resistant depression marks the next step in our understanding of and ability to treat treatment-resistant depression. The origin of ketamine is rooted in the search for a phencyclidine analog that could be used as a pre-surgical anesthetic with less emergence delirium. Following its inception, ketamine has been used in a variety of contexts. However, it was the seminal Berman et al., 2000 study, which published positive findings from the first human trial using subanesthetic intravenous ketamine for depression. Since then, a large body of research has investigated ketamine's various proposed antidepressant mechanisms of action, and the role its pharmacokinetic properties and route of administration play in producing its antidepressant effects. The results of this research were the eventual approval of intranasal esketamine for treatment-resistant depression by the U.S. Food and Drug Administration (FDA) in March 2019. By identifying and utilizing predictors of response, we can continue to refine our approach to treating treatment-resistant depression and optimize patient response to intranasal esketamine. In this article, we look at the history, pharmacology, landmark studies, and future implications of intranasal esketamine for treatment-resistant depression.