Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include alpha-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others. Published by Elsevier Ltd.