Clinical practice and data from literature indicate that up to 30% of the patients suffering from depression meet criteria for treatment-resistant depression. In the past decade, interest in the use of NMDA receptor modulators in the treatment of treatment-resistant depression is increasing. The use of ketamine an noncompetitive antagonist of the NMDA receptors, allows some patients suffering from treatment resistant depression to achieve rapid and significant improvement. The authors reviewed results of clinical studies, series of cases and case reports on the use of ketamine. Most of the patient suffered from the treatment-resistant major depression. Neurobiological basis of the glutaminergic pathways and the postulated role of glutamate in mood modulation have been described, as well as possible adverse events associated with ketamine infusion. Concerns relate to the optimal dosage, frequency of administration, long-term safety and efficacy of the therapy. Interesting results of the published articles encourage further studies on therapeutic use of NMDA receptor modulators in the treatment of treatment-resistant depression.