Major depressive disorder (MDD) is a severe and debilitating mental illness with a very largesocioeconomic impact worldwide. The neurobiology of this disease has been studied for along time, focused on neuron alterations; however, the underlying etiology is not yet full yunderstood. Astrocytes, a glial cell type, have been shown to play relevant roles modulating synaptic transmission and plasticity,with significant impact on animal behavior. Evidence collected from human samples and animal models have shown that astrocytes shown particular alterations that might contribute to the pathophysiology of MDD. We will discuss recent data showing how stress-induced depression alter astrocytic Ca2+ signalling from medial prefrontal cortex both in vivo and ex-vivo, and also the 5HT-driven cortical synaptic plasticity. We will disucss about the impact of modulating astrocytic Ca2+ signalling for animal behaviour, showing the critical balance between astrocyte Ca2+ signalling and cognitive performance, and the potential role of astrocytes as therapeutic targets in depressive-like states.