Animal studies and pharmacological studies in man have suggested that the serotonin 5-HT(1A) receptor may serve as a biomarker for cognitive functioning and a target for treatment of cognitive impairment. Consistent findings in man have nonetheless hitherto remained sparse. Positron emission tomography (PET) imaging of the 5-HT(1A) receptor in patients with Alzheimer's disease, schizophrenia and depression implicate an alteration in 5-HT(1A) receptor binding compared to control subjects, but it is yet unknown whether these alterations are related to the cognitive impairment associated with these disorders. Pharmacological challenge studies using 5-HT(1A) agonism and antagonism to manipulate the serotonin system support involvement of the 5-HT(1A) receptor in human cognition, mainly in verbal memory functioning. However, the effect varies across studies and it remains unclear if the 5-HT(1A) receptor serves as a validated target for treatment of cognitive deficits. This lack of confirmation of experimental preclinical data, calls for increased efforts in translational research. Molecular imaging techniques such as PET, holds the potential to facilitate translational neuroscience by confirming observations from animal models in man, and aid development of validated animal models of use for advancement of pharmacological treatment. Furthermore, in combination with molecular genetics, molecular imaging may suggest novel strategies for prevention and intervention, based on an understanding of the molecular mechanisms involved in disease pathogenesis of major neuropsychiatric disorder and associated cognitive impairment.