Depression is a mood disorder characterized by symptoms such as sadness, loss of interest, feelings of guilt, anhedonia, low self-esteem and poor concentration, and it is believed that as many as 4.7% of the world's population suffer from this widespread mental illness. Depression may be caused by hypothalamic-pituitary-adrenal axis dysfunction, glutamate hyperfunction, abnormal expression of brain derived neurotrophic factor, and abnormalities of the monoamine system in the central nervous system. All current antidepressants on the market can take 3 to 4 weeks to become effective, and apart from a wide spectrum of adverse effects that negatively affect patient compliance, there is a large number of patients who are resistant to existing pharmacotherapy. Therefore, finding new, more successful antidepressants is an imperative for researchers, clinicians and patients. The leader of a potential new generation of antidepressants with a fast (immediate) antidepressant effect is ketamine, but due to side effects such as psychotomimetic and dissociative effects as well as potentials of abuse, more tolerable and safer medications are required. By studying the mechanism of action, it was shown that ketamine noncompetitively blocks glutamate NMDA receptor and activates AMPA receptor, and new compounds were synthesized to work with that mechanism. Given the structural characteristics of the NMDA ionotropic receptor and possible different binding sites for the ligands on that protein complex, target compounds are designed which should more or less selectively act on a particular binding site and consequently modulate intracellular signaling in a manner that ultimately results in satisfactory antidepressant effect, with the absence of typical side effects. Most studies have been conducted with compounds designed as antagonists of the GluN2B subunit of the NMDA receptor. However, although they have entered into clinical trials, neither traxoprodil nor rislenemdaz have met primary therapeutic goals. The most promising group of compounds are modulators of the glycine site of the NMDA receptor. The partial glycine site agonist rapastinel and its analogue for oral administration apimostinel show satisfactory results in the phases of clinical research and the expectations of the scientific public are greatest for those compounds. Metabotropic glutamate receptor (mGluR) modulators, with the exception of the negative allosteric modulator basimglurant still being evaluated in clinical studies, did not show a satisfactory antidepressant effect and development of nearly all of them was discontinued. The search for a new antidepressant with an ideal pharmacological and therapeutic profile seems to be a big challenge, but the results of the research give hope that in the near future we will be able to talk about depression as a successfully treated illness for all patients.