Numerous studies have demonstrated the efficacy of (R,S)-ketamine as a treatment for posttraumatic stress disorder (PTSD) (1), treatment resistant depression (2, 3), and co-morbid occurrences of these conditions (4). The (R,S), (R), and (S) stereoisomers of ketamine have also demonstrated efficacy in attenuation of stress and depressive symptoms (5), with (R)-ketamine demonstrating reduced abuse potential and side effects (6). Although research on (R,S)-ketamine’s and its metabolites’ efficacy has been promising, less is known about the mechanisms by which these compounds elicit their therapeutic effects. Here, we review the research literature concerning the hypothesized mechanisms of (R,S)-ketamine and its metabolites. The pharmacodynamics of (R,S)-ketamine’s effects on depression involve the dentate gyrus, prefrontal cortex, hippocampal CA3, dorsal raphe nucleus, and the prelimbic to dorsal raphe nucleus (PL-DRN) circuit. The current evidence suggests that, although brain-derived neurotropic factor (BDNF) expression through activation of tropomyosin-related kinase B (TrkB) is likely necessary for (R,S)-ketamine’s therapeutic effects, NMDA receptor antagonism may be unrelated to its antidepressant efficacy.