Alterations in serotonergic activity have been observed in many pathological conditions, including neuropsychiatric diseases, irritable bowel syndrome, and hypertension. The serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT) in the brain clears 5-HT from extracellular spaces, modulating the strength and duration of serotonergic signaling. Outside the central nervous system, it is also present in platelets, where it takes up 5-HT from plasma, keeping levels very low (i.e., ~1 nM). Importantly, it is generally accepted that SERT protein expressed in platelets is identical to the one found in neurons, displaying similar structural and functional properties in both tissues. At the present time, it is technically difficult to measure SERT binding and function in vivo since imaging methods are limited by a number of factors, especially the cost and the selectivity of the available radioligands. One of the most frequently used molecular imaging techniques to study SERT is positron emission tomography (PET). Although an impressive number of PET radioligands have been synthesized and validated, there is still a lack of suitable ligands for a large part of the 5-HT system. Interest in determining both the molecular characteristics and the regulation of SERT has been enormous over the last decade, but the difficulty in obtaining human tissues and the ethical limitations in human experiments have turned researchers to look for alternative models. This review summarizes recent clinical and preclinical data relevant to the use of blood platelets as a peripheral marker for the central 5-HT system, and outlines future directions in this field.