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Modulating serotonergic signalling in the brain is the target of current first-line pharmacological approaches for the treatment of anxiety and depression.  However, treatments such as SSRIs have considerable limitations, including a slow onset of their therapeutic effects and a lack of efficacy in treating some symptom clusters, in particular anhedonia and cognition.  Emerging animal and human evidence suggests that specifically activating serotonin 4 receptors (5-HT4R) may be a promising target with the potential to provide more rapid, efficacious therapeutic effects.  In preclinical models, 5-HT4R agonists rapidly reduce behavioural despair, anhedonia, and anxiety-like behaviour, and increase resilience to stress.  Interest in this receptor has recently been stimulated by new evidence highlighting the key role that this receptor plays in human mood and cognition. In this seminar we will present human behavioural, neuroimaging and pharmacoepidemiological evidence, which has converged to demonstrate the considerable promise the 5-HT4R holds as a novel target for the treatment of depression, and in particular for treating the cognitive symptoms of the disorder which are not well addressed by conventional treatments.