The discovery of ketamine's rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild-to-moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment are not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders.