Major depressive disorder (MDD) is among the most common mental health problems in the U.S. and the world. A significant portion of patients with MDD do not respond to current antidepressant medications and are considered treatment-resistant. Current antidepressant therapies have a late onset of action that causes significant challenges when treating patients with suicidal ideation. In the past two decades, there has been significant interest in the anesthetic drug ketamine as an antidepressant. Evidence suggests that ketamine is effective even in treatment-resistant patients, with rapid onset of benefits observed hours after administration. The U.S. Food and Drug Administration has recently approved a nasal spray containing the S-enantiomer of ketamine, or esketamine, as an antidepressant therapy. This thesis reviewed the literature on both ketamine and esketamine as antidepressants, with a focus on the two most commonly used routes of administration, intravenous infusion and intranasal administration. This study concludes that both ketamine and esketamine have robust and rapid antidepressant effects. Both formulations are safe and well tolerated by patients, with transient, nonserious side effects easily managed and monitored by healthcare providers. Further research should focus on broadening the availability of ketamine and esketamine to patients.