The circulatory system consists of veins and arteries. Compared with arteries, veins have been neglected in cardiovascular research. Although veins are significantly less muscular than similarly sized arteries, the contribution of veins to cardiovascular homeostasis cannot be left un-noted because veins accommodate 70% of the circulating blood. Circulating blood platelets contain the majority of systemic 5- HT ( 5- hydroxytryptamine; serotonin). Similar to venous function, the physiological role of 5- HT in the cardiovascular system is not well understood. Here, we present not only a review on 5- HT and veins but ways in which these two topics might intersect in a physiologically relevant manner. Here we show the novel findings that veins exhibit higher amounts of intracellular 5- HT than arteries. Moreover, we also show evidence that, similar to arteries, veins have the ability to uptake 5- HT. In this review, we introduce the venous system as a reservoir for 5- HT in the periphery, suggesting that veins, in addition to arteries, may represent an important target for drugs that interfere with the serotonergic system. In addition, the serotonergic system from synthesis to metabolism, 5- HT receptor activation and venous diseases will also be discussed.