Despite the fact that antidepressants represent the gold standard for the treatment of depression, not all patients treated with an antidepressant monotherapy achieve complete remission of depressive symptoms and functional recovery. Therefore, further examination of the components that may be involved in the action mechanism of antidepressants will benefit patients who show either no response or partial response by identifying their hidden functions and key roles in the therapeutic mechanism of antidepressants. The cocaine- and amphetamine-regulated transcript (CART), which is a brain-enriched mRNA with a protein product(s) is an interesting neuropeptide in relation to the treatment of depression. CART mRNA is strongly expressed in the major limbic structures that modulate affect and anxiety as well as being a possible key target for the action of antidepressants. A bidirectional relationship between CART and the hypothalamic-pituitary-adrenal (HPA) axis activity has been accepted to date, which suggests that CART might efficiently bridge the interaction between the stress-related events and the neurobehavioral response. The regulation of the signal transduction pathways by CART by modulating neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), kinases (trkB), and neurotransmitters (5-HT), can also contribute to the treatment of depression. It might have an augmenting effect in the treatment of depression because it acts as a putative and potential neurotransmitter/cotransmitter that is involved in psychostimulant action as well. Finally, preliminary results suggest that CART directly controls the expression of major neurotransmitters such as serotonin, noradrenaline, and dopamine. Hence, further studies on therapeutic implications of CART for depression are warranted and will contribute to the development of newer selective antidepressants.