Major depressive disorder (MDD) is estimated to impose maximum debilitating effects on the society by 2030, with its critical effects on health, functioning, quality of life and concomitant high levels of morbidity and mortality. Yet the disease is inadequately understood, diagnosed and treated. Moreover, with the recent drastic rise in pace of life, stress has materialized as one of the most potent environmental factor for depression. In this scenario, it is important to understand the modern pathogenetic hypotheses and mechanisms, and possibly try to shift from the traditional approaches in depression therapy. These include elaboration of pathophysiological changes in the heterogeneous systems such as genetic, epigenetic, serotonergic, noradrenergic, gamma-aminobutyric acid, glutamergic and endocannabinoid systems, neurotrophic factors, HPA axis, immune system as well as cellular stress mechanisms. These components interact with each other in a complex matrix and further elucidation of their mechanism and cascade pathways are needed. This might aid in identification of MDD subtypes as well as development of sophisticated biomarkers. Further characterization might also aid in developing multitargeted therapies that hold much promise as compared to the conventional monoamine based treatment. New candidate pharmacons, refined psychotherapeutic modalities, advanced neuro-surgical and imaging techniques as well as implementation of pharmacokinetic, pharmacogenetic prescribing guidelines constitute the emerging expanses of MDD treatment.