Treatment-resistant depression (TRD) is a challenging condition with low response and remission rates. Intranasal esketamine (ESK) is the first regulatory-approved medication specifically designed for difficult-to-treat depression that builds upon the discovery of rapid antidepressant effects of intravenous (IV) racemic ketamine. For more than 6 years now, ESK has demonstrated efficacy, safety, and practicality in acute and long-term management of TRD and major depressive disorder with suicidal ideation or behavior. This chapter builds upon the insights gained in patient trials and clinical experience with ESK and will discuss emerging indications, future research, and paths forward in clinical practice. Potential new indications include approaches to improve neurocognitive performance, even in the elderly, and to provide better care in posttraumatic stress and substance use disorders, in depressed youth as well as in bipolar depression. In everyday care, IV racemic ketamine can be used in acute situations, before a transition to ESK is feasible. For outpatient practice, new combinations such as with dextromethorphan/bupropion and sometimes magnesium have emerged. Ketamine’s side effects can induce beneficial subjective experience especially with patient preparation and guidance through psychoactive events and appropriate behavioral or augmented psychotherapy.