The decision-making process for or against intravenous (IV) racemic ketamine versus intranasal (IN) esketamine is a critical choice in therapeutic approaches for treatment-resistant depression (TRD). This chapter draws upon real-world data gathered from a specialized center for depression treatment at the Mayo Clinic in Rochester, Minnesota, USA, to examine important factors which may determine this selection. In the acute phase, IV racemic ketamine and IN esketamine demonstrated similar response and remission rates; however, IV racemic had an accelerated response compared to IN esketamine. Additionally, both treatments were well-tolerated by patients.