It is firmly believed that the mechanism of action of SSRIs in major depression is to inhibit the serotonin transporter, SERT, and increase extracellular concentration of serotonin. However, this undisputed observation does not prove that SERT inhibition is the mechanism, let alone the only mechanism, by which SSRI’s exert their therapeutic effects. It has recently been demonstrated that 5-HT 2B receptor stimulation is needed for the antidepressant effect of fluoxetine in vivo. The ability of all five currently used SSRIs to stimulate the 5-HT 2B receptor equipotentially in cultured astrocytes has been known for several years, and increasing evidence has shown the importance of astrocytes and astrocyte-neuronal interactions for neuroplasticity and complex brain activity. This paper reviews acute and chronic effects of 5-HT 2B receptor stimulation in cultured astrocytes and in astrocytes freshly isolated from brains of mice treated with fluoxetine for 14 days together with effects of anti-depressant therapy on turnover of glutamate and GABA and metabolism of glucose and glycogen. It is suggested that these events are causally related to the mechanism of action of SSRIs and of interest for development of newer antidepressant drugs.