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Although it is a coincidence that publication of the main findings of the seminal STAR*D study coincided with the 20th anniversary of the introduction of fluoxetine, the “graying” of the second generation of antidepressants has been accompanied by recognition of many critical unmet needs. The relatively underwhelming results of the sequential stages of STAR*D underscored that there is a great need for therapies for depressed patients who do not respond to first- and second-line antidepressants. Perhaps the progressive decrement in remission rates observed across stages in STAR*D reflects the fact that all of the medications studied initiate antidepressant action through monoaminergic mechanisms. This talk will briefly overview of several alternate targets for novel medications, focusing primarily on the glutamatergic system. The rapid antidepressant effects of the dissociative anesthetic ketamine, initially observed serendipitously in the late 1990s, have now been widely replicated and set the stage for a new generation of drug discovery. Research pertaining to several other investigational antidepressants that modulate glutamatergic neurotransmission, including esketamine, raspastinel and lanicemine, will be summarized. There are several concerns and unanswered questions pertaining to durability of therapeutic effects and safety that warrant careful long-term study. Nevertheless, for the first time since the discovery of imipramine and iproniazid in the mid-1950s, truly paradigm shifting antidepressant medications appear to be on the horizon.