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Treatment-resistant depression, defined as a failure of at least two oral antidepressants of adequate dose and duration in the current episode, is a debilitating condition with low rates of response and remission. Intranasal esketamine is the first medication approved by regulatory authorities for difficult to treat depressive episodes that builds directly on the discovery of the rapid antidepressant effects of intravenously administered racemic ketamine. Approved in the United States in 2019, and subsequently, in many countries worldwide, intranasal esketamine is indicated in conjunction with any new or previously taken oral antidepressant medication of the clinician’s choosing for treatment-resistant depression in adults. It is also indicated for the treatment of major depressive disorder in adults with acute suicidal ideation or behavior who may or may not be treatment-naive or have treatment-resistant depression. This article outlines the case for the efficacy, safety profile, and feasibility of acute, short-term intranasal esketamine followed by the long-term continuation of intranasal esketamine versus long-term off-label intravenous ketamine in treatment-resistant depression. The article further suggests biomarkers to predict response that warrant further study.