For decades, dysfunctional serotonergic, noradrenergic, and dopaminergic have been perceived as the cause of depressive disorders. The discovery of the role of astroglial cells on human and mice subjects has revealed that these cells do much more than provide maintenance for physiological functions in the Central Nervous System (CNS). Recent studies have suggested that astroglial cells may reduce the presynaptic release of neurotransmitters or inhibit signal transductions. In this succinct commentary, we examine the role of astroglial cells on neurotransmitters, human post-mortem studies on patients with major depressive disorder, animal studies evaluating Ca2+ signaling in astrocytes, and the possible function of antidepressants on astroglial cells.