Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder. Current medication for the treatment of depression have limited efficacy and delayed onset of therapeutic action. In view of the limitation of the current antidepressant pharmaceuticals, tremendous research efforts are ongoing to search for a pharmacological treatment which may improve antidepressive efficacy, onset of action or even both therapeutic parameters. To address these needs, numerous combination therapies that maintain the benefits associated with selective serotonin reuptake inhibitors (SSRIs) but attempts to improve efficacy or reduce side effects by additional mechanism (5-HT1A, 5-HT2C ) and newer approaches targeting excitatory (glutamate, NMDA,mGluR2, mGluR5) or inhibitory aminoacid system (GABA) or peptidergic system(neurokinin1, corticotrophin releasing factor1, melanin concentrating hormone1) have been identified. The goal of this review is to give a brief overview of the major advances in monoamine based treatment strategies and the new emerging approaches in the treatment of depression.