Serotonin, also known as 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter in the central nervous system (CNS), but also plays a significant role in peripheral tissues. There is a growing body of evidence suggesting that serotonin influences immune cell responses and contributes to the development of pathological injury in cardiovascular diseases, such as atherosclerosis, as well as other diseases which occur as a result of immune hyperactivity. In particular, high levels of serotonin are able to activate a multitude of 5-HT receptors found on the surface of immune cells, thereby influencing the process of atherosclerotic plaque formation in arteries. In this review, we will discuss the differences between serotonin production in the CNS and the periphery, and will give a brief outline of the function of serotonin in the periphery. In this context, we will particularly focus on the effects of serotonin on immune cells related to atherosclerosis and identify caveats that are important for future research.