In spite of more than 40 years of thorough studies, conventional antidepressants still have many limitations that hinder the effective treatment of depression. It seems that a breakthrough in the therapy of depression will require going beyond a monoamine-based theory of depression. Converging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy. Both ionotropic glutamate receptor ligands (functional NMDA receptor antagonists and AMPA receptor potentiators) and compounds acting at metabotropic glutamate receptors (mGluRs; group I mGluR antagonists, group II antagonists and group III agonists) produce antidepressant-like activity in several preclinical and some clinical studies. In this review, current knowledge and crucial hypotheses concerning the role of glutamate in the pathophysiology of depression are discussed.