The 5-HT7 receptor has recently received considerable attention since its involvement has been implicated in cognitive disturbances, sleep and circadian rhythmicity disorders, anxiety and depression. At the cellular level, 5-HT7 receptors increase the excitability of excitatory cells and appear to modulate both glutamatergic and GABAergic transmission in the hippocampus. It has been proposed that 5-HT7 receptors also modulate glutamatergic and GABAergic transmission in the raphe nuclei and these effects may play a role in the regulation of circadian rhythms. Repeated administration of the selective 5-HT7 receptor antagonist induced functional desensitization of the 5-HT7 receptor system at the level of its reactivity and effector proteins. These effects resemble the outcome of treatment of rats with antidepressant drugs. Chronic stress and elevated level of corticosterone increase the reactivity of 5-HT7 receptors in the hippocampus. Treatment of rats with a selective 5-HT7 receptor antagonist also results in attenuation of glutamatergic transmission in the frontal cortex and it prevents the occurrence of stress-induced modifications of glutamatergic transmission and long-term synaptic plasticity. These results are consistent with the hypothesis that 5-HT7 receptor antagonism might, potentially, be used for the treatment of cognitive deficits and mood disorders.