Clinical depression can be highly treatment resistant in some cases, but ketamine has been shown to relieve depressive symptoms in even many treatment-refractory cases. Ketamine appears to work via a novel mechanism since it 1) treats many patients not affected by other treatments and 2) has a temporal profile of action unlike any other medication: a drug metabolized within hours has rapid-onset action that lasts for days. However, despite it's efficacy over initial weeks of treatment, over months, it's efficacy falls off and further work is needed to best determine how to use this short and medium term efficacy, or to determine how to lengthen it. Importantly, the new mechanism of action of ketamine opens up new avenues to understand the mechanisms of depression, which may lead to yet more novel therapies.