Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.