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The “serotonin hypothesis of depression” is approximately fifty years old, and in spite of vast literature, the exact role of serotonin in depression pathophysiology is still unclear, as whether a lower serotonin level causes depression or depression causes a reduction in serotonin level has become a tough challenge for researchers to understand the actual involvement of serotonin in depression. Several pre-clinical and clinical studies have illustrated the multi-faceted signalling action of serotonin in depression and vouch for the significant or unavoidable role of serotonin in depression. In this review, the journey of the serotonin hypothesis of depression from the 1950s to the present time has been analysed to understand the serotonin hypothesis of depression and investigate the new molecular targets for the development of new future anti- depressants. The old and new theories of possible cellular mechanisms found to be involved in the pathophysiology of major depression or stress, such as polymorphism of serotonin transporters, enzyme modulating serotonergic activity, reduction in the level of serotonin and involvement of different sub-types of receptors, have been discussed in the respective review. Thus, in this review, the new signature targets to increase serotonin levels have been identified, which would help the researcher in the drug development of new faster-acting antidepressants.