Recent evidence, such as that from the STAR-D study, have demonstrated that several unmet needs are still present in the treatment of major depression. The “classical” approach adopted to develop new antidepressants drugs, based on selectivity, did not result in increased remission rates in clinical practice, whereas multi-modality represents a new approach to develop novel antidepressants endowed with multiple actions that affect several pharmacological targets. Multimodal antidepressants, developed in the last three years, act through at least two pharmacological modes of action (serotonin reuptake inhibition, agonist/antagonists on neurotransmitter receptors) on at least two or more pharmacologic targets. Vortioxetine is a novel multimodal antidepressant that exerts its antidepressant efficacy in animal models of depression through a combination of two pharmacological modes of action: reuptake inhibition and receptor activity. In vitro studies indicate that vortioxetine is antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist of 5-HT1B receptors, an agonist of 5-HT1A receptors, and inhibitor of the serotonin transporter. The combination of 5-HT1A agonism with 5-HT3 antagonism can explain the rapid 5-HT cell firing induced by vortioxetine compared to SSRIs such as fluoxetine. Vortioxetine is also able to activate the glutamatergic system in the rat frontal cortex through antagonism at 5-HT3, 5-HT7 receptors. All these pharmacological modes of action can contribute to explain the increased clinical efficacy of vortioxetine in the treatment of cognitive symptoms of depression. Cognitive deficits in depression are often associated with both a suboptimal response to antidepressants and reduced remission rates. Vortioxetine is the first multimodal antidepressant available for the treatment of depression with a specific, positive impact on cognitive symptoms.